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

Abstract

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.

Recent Advancements in Transition‐Metal‐Catalyzed One‐Pot Twofold Unsymmetrical Difunctionalization of Arenes

“…In 2017, Ackermann group implemented highly position selective chelation assisted meta ‐C−H functionalizations to furnish an array of meta ‐decorated aromatics via an uncommon arene ligand effect of PhCMe 3 in proximity‐induced ruthenium(II)‐catalysis (Scheme ) . Two examples of tandem multicatalysis were also showcased through a sequential remote meta ‐C−H alkylation followed by ortho ‐C−H arylation/alkylation in a one‐pot fashion with the aid of a single catalyst using 3,4,5‐trimethoxyphenyl (TMP) derived ketimine as a directing group.…”

Jenseits von Friedel und Crafts: dirigierte Alkylierung von C‐H‐Bindungen in Arenen

“…(2)].D ie grçßte Einschränkung war der erforderliche Überschuss an Grignard-Reagens,d er die tolerierten funktionellen Gruppen deutlich begrenzt. [68] Mit einem Katalysesystem, das dem mit primären Alkylbromiden verwendeten stark ähnelte,e rfolgte eine saubere meta-selektive Alkylierung von TMP-Iminen. Dieses Verfahren wurde weiter auf die Umsetzung von Pivalophenon-N-H-Iminen ausgeweitet, die sich als hervorragende Benzonitrilsurrogate fürdirigierte C-H-Alkylierungen erwiesen, bei denen die entsprechenden Benzonitrile in einem Folgeschritt entweder durch Bestrahlung in Gegenwart eines Peroxids oder durch Reaktion mit einer katalytischen Mengen an Kupfer(II)-acetat unter aeroben Bedingungen hergestellt wurden.…”

S‐Adenosyl Methionine Cofactor Modifications Enhance the Biocatalytic Repertoire of Small Molecule C‐Alkylation

“…In this instance,t he conversion of 5 to 5a improved to 85 %( 4h)a nd 77 %( 4j)r elative to 49 %w hen SAM was generated in situ ( Figure 5). Exploration of the wider scope of methylating (5a-13 a)a nd ethylating (5b-13 b)asuite of 3-substituted coumarins (5)(6)(7)(8)(9)(10)(11)(12)(13)e xemplified the superiority of using nucleobase-modified SAM/SAE analogues ( Figure 6). [34] The2 -modified alkyne cofactor 4i displayed comparable conversion (5a,5 0%)t oS AM, whereas the formation of the 2-amino-6-chloro analogue (4g)i nsitu did not form 5a.…”

“…[3] In order to fully exploit this "magic methyl effect" across the pharmaceutical and biotechnology sectors, [4,5] robust methods are required to precisely methylate-and indeed alkylate-substrates in an environmentally benign manner. [11][12][13] However,o btaining regiospecificity,p articularly when this is required at alate-stage in asynthetic workflow,is an enduring challenge. [11][12][13] However,o btaining regiospecificity,p articularly when this is required at alate-stage in asynthetic workflow,is an enduring challenge.…”