Cyclometallated ruthenium catalyst enables late-stage directed arylation of pharmaceuticals

Abstract

Biaryls are ubiquitous core structures in drugs, agrochemicals and organic materials that have profoundly improved many aspects of our society. Although traditional cross-couplings have made practical the synthesis of many biaryls, C-H arylation represents a more attractive and cost-effective strategy for building these structural motifs. Furthermore, the ability to install biaryl units in complex molecules via late-stage C-H arylation would allow access to valuable structural diversity, novel chemical space and intellectual property in only one step. However, known C-H arylation protocols are not suitable for substrates decorated with polar and delicate functionalities, which are commonly found in molecules that possess biological activity. Here we introduce a class of ruthenium catalysts that display a unique efficacy towards late-stage arylation of heavily functionalized substrates. The design and development of this class of catalysts was enabled by a mechanistic breakthrough on the Ru(II)-catalysed C-H arylation of N-chelating substrates with aryl (pseudo)halides, which has remained poorly understood for nearly two decades.

meta‐Selective C−H Activation of Arenes at Room Temperature Using Visible Light: Dual‐Function Ruthenium Catalysis

“…Zuschriften Based on the above results and literature observations on Ru-meta chemistry, [9,12] ap ossible mechanism is shown in Scheme 3. Blue-light irradiation of the in situ formed Ru II cyclometalated complex B generates al ong-lived excited state of the Ru II complex C,w hich can undergo SET to the alkyl halide (X = Br or I) and form aC -centered radical and the Ru III -cyclometalated complex D.I nt he next step,t he nucleophilic carbon-centered alkyl radical then undergoes ar adical attack on para position to electrophilic D to afford the complex E.Recent computational work from Ackermann and co-workers has implicated Ru III as having substantially higher selectivity in this step than Ru II ,i nl ine with the proposed electron-transfer step from Ru II to alkyl halide.…”

Sustainable Knowledge‐Driven Approaches in Transition‐Metal‐Catalyzed Transformations

“…The employment of knowledge‐driven approaches for the synthesis of complex organic scaffolds represents one of its most promising applications. In 2018, Larrosa and co‐workers described the rational design of a new family of ruthenium catalysts capable of promoting the late‐stage C−H arylation of highly decorated N‐chelating molecules, including pharmaceuticals, agrochemicals, or natural products, with aryl(pseudo)halides . In this work, the authors demonstrated how a fundamental mechanistic understanding could play a crucial role in the development of more efficient transformations.…”

“…In this work, the authors demonstrated how a fundamental mechanistic understanding could play a crucial role in the development of more efficient transformations. A thorough mechanistic investigation of the previously proposed Ru II/IV catalytic cycle allowed them to uncover key unprecedented mechanistic features: 1) p ‐cymene type‐ligands (e.g., 1 Ru ‐MeCN ; Scheme ), widely used in these Ru‐catalyzed transformations, inhibited the directed arylation reaction; 2) the employment of a p ‐cymene‐free ruthenacycle, 2 Ru ‐MeCN , afforded faster product formation; and 3) the formation of a bis‐cycloruthenated Ru II intermediate, 3 Ru ‐MeCN , prior to the oxidative addition step, was confirmed, which revealed that a second C−H activation step occurred before accessing the high‐valent Ru IV species (Scheme ). Based on their experimental results, the authors proposed a new mechanistic hypothesis, which involved a bis‐cycloruthenated intermediate, as an alternative to the widely accepted catalytic cycle (Scheme ).…”

Aren‐freie Ruthenium(II/IV)‐katalysierte gegabelte Arylierungen für oxidative C‐H/C‐H‐Funktionalisierungen

“…[18] Dabei wurden unabhängig von der Art der verwendeten Substrate 1 und 2 vergleichbare Resultate erhalten (Abbildungen S-4-S-6 in den Hintergrundinformationen). Diese Beobachtungen lassen stark auf einen katalytisch aktiven, Aren-Ligand-freien Komplex schließen (Abbildung 3).…”