Palladium catalyzed meta-C-H functionalization enabled by transient mediators has the potential to extend the utility of directed ortho-C-H functionalization to remote positions. However, there have been no reports of palladium catalyzed meta-C-H functionalization of aromatic aldehyde derivatives, which are highly versatile intermediates in organic synthesis. Herein we report the development of a directing group that, in the presence of a norbornene derived mediator and an appropriate pyridone ligand, allows palladium catalyzed meta-C-H functionalization of masked aromatic aldehydes. Mechanistic insight regarding the impact of the directing group length on this catalysis is also discussed.

The meta-C-H arylation of free phenylacetic acid was realized using 2-carbomethoxynorbornene (NBE-CO2 Me) as a transient mediator. Both the modified norbornene and the mono-protected 3-amino-2-hydroxypyridine type ligand are crucial for this auxiliary-free meta-C-H arylation reaction. A series of phenylacetic acids, including mandelic acid and phenylglycine, react smoothly with various aryl iodides to provide the meta-arylated products in high yields.

Meta-C-H functionalization of benzylamines has been developed using a PdII /transient mediator strategy. Using 2-pyridone ligands and 2-carbomethoxynorbornene (NBE-CO2 Me) as the mediator, arylation, amination, and chlorination of benzylamines are realized. This protocol features a broad substrate scope and is compatible with heterocylic coupling partners. Moreover, the loading of the Pd can be lowered to 2.5 mol % by using the optimal ligand.

A range of Rh(III)-catalyzed ortho-C-H functionalizations have been developed; however, extension of this reactivity to remote C-H functionalizations through large-ring rhodacyclic intermediates has yet to be demonstrated. Herein we report the first example of the use of a U-shaped nitrile template to direct Rh(III)-catalyzed remote meta-C-H activation via a postulated 12-membered macrocyclic intermediate. Because the ligands used for Rh(III) catalysts are significantly different from those of Pd(II) catalysts, this offers new opportunities for future development of ligand-promoted meta-C-H activation reactions.

We herein report the first example of a 2-pyridoneaccelerated non-directed C−H cyanationwith an arene as the limiting reagent. This protocol is compatible with a broadscope of arenes, including advanced intermediates, drug molecules, and naturalproducts. A kinetic isotope experiment (kH/kD = 4.40)indicates that the C–H bond cleavage is therate-limiting step. Also, thereaction is readily scalable, further showcasing the synthetic utility of thismethod.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

A Pd-catalyzed, meta-selective C-H arylation of nosyl-protected phenethylamines and benzylamines is disclosed using a combination of norbornene and pyridine-based ligands. Subjecting nosyl protected 2-aryl anilines to this protocol led to meta-C-H arylation at the remote aryl ring. A diverse range of aryl iodides are tolerated in this reaction, along with select heteroaryl iodides. Select aryl bromides bearing ortho-coordinating groups can also be utilized as effective coupling partners in this reaction. The use of pyridine ligands has allowed the palladium loading to be reduced to 2.5 mol %. Furthermore, a catalytic amount of 2-norbornene (20 mol %) to mediate this meta-C-H activation process is demonstrated for the first time. Utilization of a common protecting group as the directing group for meta-C-H activation of amines is an important feature of this reaction in terms of practical applications.

Using a modified norbornene (methyl bicyclo[2.2.1]hept-2-ene-2-carboxylate) as a transient mediator, meta-C-H amination and meta-C-H alkynylation of aniline and phenol substrates have been developed for the first time. Both the identification of a monoprotected 3-amino-2-hydroxypyridine/pyridone-type ligand and the use of a modified norbornene as a mediator are crucial for the realization of these two unprecedented meta-C-H transformations. A variety of substrates are compatible with both meta-C-H amination and meta-C-H alkynylation. Amination and alkynylation of heterocyclic substrates including indole, indoline, and indazole afford the desired products in moderate to high yields.

Here we report the development of a versatile 3-acetylamino-2-hydroxypyridine class of ligands that promote meta-C-H arylation of anilines, heterocyclic aromatic amines, phenols, and 2-benzyl heterocycles using norbornene as a transient mediator. More than 120 examples are presented, demonstrating this ligand scaffold enables a wide substrate and coupling partner scope. Meta-C-H arylation with heterocyclic aryl iodides as coupling partners is also realized for the first time using this ligand. The utility for this transformation for drug discovery is showcased by allowing the meta-C-H arylation of a lenalidomide derivative. The first steps toward a silver-free protocol for this reaction are also demonstrated.

Achieving selective C-H activation at a single and strategic site in the presence of multiple C-H bonds can provide a powerful and generally useful retrosynthetic disconnection. In this context, a directing group serves as a compass to guide the transition metal to C-H bonds by using distance and geometry as powerful recognition parameters to distinguish between proximal and distal C-H bonds. However, the installation and removal of directing groups is a practical drawback. To improve the utility of this approach, one can seek solutions in three directions: 1) Simplifying the directing group, 2) using common functional groups or protecting groups as directing groups, and 3) attaching the directing group to substrates via a transient covalent bond to render the directing group catalytic. This Review describes the rational development of an extremely simple and yet broadly applicable directing group for Pd(II) , Rh(III) , and Ru(II) catalysts, namely the N-methoxy amide (CONHOMe) moiety. Through collective efforts in the community, a wide range of C-H activation transformations using this type of simple directing group have been developed.

AbstractDie selektive C‐H‐Aktivierung an einer einzigen und strategisch wichtigen Position in Gegenwart von zahlreichen weiteren C‐H‐Bindungen kann einen leistungsfähigen und allgemein nützlichen Schritt in der Syntheseplanung darstellen. In diesem Zusammenhang dient die dirigierende Gruppe als ein “Kompass”, um – mittels Abständen und Geometrien als Erkennungsparameter zur Unterscheidung zwischen proximalen und distalen C‐H‐Bindungen – das Übergangmetall an C‐H‐Bindungen zu lenken. Die Einführung und Abspaltung dirigierender Gruppen ist allerdings ein Nachteil für die Synthesepraxis. Um diese Ansätze nützlicher zu gestalten, kann man in drei Richtungen nach Lösungen suchen. Erstens, durch Vereinfachung der dirigierenden Gruppe; zweitens, durch Verwendung von gängigen funktionellen Gruppen oder Schutzgruppen als dirigierende Gruppen; drittens, durch Anbindung der dirigierenden Gruppe an Substrate über eine transiente kovalente Bindung, um die dirigierende Gruppe zu einem Katalysator zu machen. Dieser Aufsatz beschreibt die rationale Entwicklung einer sehr einfachen und dennoch breit anwendbaren dirigierenden Gruppe für PdII‐, RhIII‐ und RuII‐Katalysatoren, nämlich die N‐Methoxyamidgruppe (CONHOMe). Eine Vielzahl von Transformationen unter C‐H‐Aktivierung wurde mithilfe dieser einfachen dirigierenden Gruppen bereits entwickelt.

Pd-catalyzed meta-C-H chlorination of anilines and phenols is developed using norbornene as the mediator. Heterocycles, including indole, thiophene, and indazole, are tolerated. The identification of a new pyridone-based ligand is crucial for the success of this meta-C-H chlorination reaction. Subsequent diverse transformations of the chlorinated products demonstrate the versatility of meta-C-H chlorination.

AbstractDiverse and high yielding ortho‐C—H functionalizations of readily available, enantiomerically pure pivaloyl‐protected mandelic acid is presented.

Pd-catalyzed C-H functionalization of mandelic acid and α-phenylglycine is reported. We have developed different protocols for the arylation, iodination, acetoxylation, and olefination of these substrates based on two different (Pd(II)/Pd(IV) and Pd(II)/Pd(0)) catalytic cycles. Four crucial features of these protocols are advantageous for practical applications. First, the α-hydroxyl and amino groups are protected with simple protecting groups such as acetates (Ac, Piv) and carbamates (Boc, Fmoc), respectively. Second, these protocols do not involve installation and removal of a directing group. Third, monoselectivity is accomplished. Fourth, no epimerization occurs at the vulnerable α-chiral centers.

In an idealistic setting, it can be imagined that if every CH bond on an organic molecule could be selectively functionalized, the fields of chemical synthesis and drug discovery would be forever revolutionized. With the purpose of investigating the practicality of this idealistic scenario, our group has endeavored to unlock the potential of nature's CH bonds by developing palladium-catalyzed, site selective CH insertions that can be incorporated into both known and new catalytic cycles. To this end, we have developed a number of catalytic transformations that not only provide rapid diversification of simple starting materials and natural products through CH functionalization, but streamline the synthesis of a variety of natural products with biological activity and expand upon methods to access highly valuable enantiopure materials.