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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 directed activation of carbon-hydrogen bonds (C-H) is important in the development of synthetically useful reactions, owing to the proximity-induced reactivity and selectivity that is enabled by coordinating functional groups. Palladium-catalysed non-directed C-H activation could potentially enable further useful reactions, because it can reach more distant sites and be applied to substrates that do not contain appropriate directing groups; however, its development has faced substantial challenges associated with the lack of sufficiently active palladium catalysts. Currently used palladium catalysts are reactive only with electron-rich arenes, unless an excess of arene is used, which limits synthetic applications. Here we report a 2-pyridone ligand that binds to palladium and accelerates non-directed C-H functionalization with arene as the limiting reagent. This protocol is compatible with a broad range of aromatic substrates and we demonstrate direct functionalization of advanced synthetic intermediates, drug molecules and natural products that cannot be used in excessive quantities. We also developed C-H olefination and carboxylation protocols, demonstrating the applicability of our methodology to other transformations. The site selectivity in these transformations is governed by a combination of steric and electronic effects, with the pyridone ligand enhancing the influence of sterics on the selectivity, thus providing complementary selectivity to directed C-H functionalization.

Meta-C–H functionalization of benzylamines has been developed using a Pd(II)/transient mediator strategy. Using 2-pyridone ligands and 2-carbomethoxylnorbornene (NBE-CO2Me) 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 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.

Pd-catalyzed meta-C–H chlorination of anilines and phenols is developed using norbornene as the mediator. The presence of 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.

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.

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.

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.

Die selektive C-H-Aktivierung an einer einzigen und strategisch wichtigen Position in Gegenwart von zahlreichen weiteren C-H-Bindungen kann einen leistungsfahigen und allgemein nutzlichen Schritt in der Syntheseplanung darstellen. In diesem Zusammenhang dient die dirigierende Gruppe als ein “Kompass”, um – mittels Abstanden und Geometrien als Erkennungsparameter zur Unterscheidung zwischen proximalen und distalen C-H-Bindungen – das Ubergangmetall an C-H-Bindungen zu lenken. Die Einfuhrung und Abspaltung dirigierender Gruppen ist allerdings ein Nachteil fur die Synthesepraxis. Um diese Ansatze nutzlicher zu gestalten, kann man in drei Richtungen nach Losungen suchen. Erstens, durch Vereinfachung der dirigierenden Gruppe; zweitens, durch Verwendung von gangigen funktionellen Gruppen oder Schutzgruppen als dirigierende Gruppen; drittens, durch Anbindung der dirigierenden Gruppe an Substrate uber 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 fur PdII-, RhIII- und RuII-Katalysatoren, namlich die N-Methoxyamidgruppe (CONHOMe). Eine Vielzahl von Transformationen unter C-H-Aktivierung wurde mithilfe dieser einfachen dirigierenden Gruppen bereits entwickelt.

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.

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.

In an idealistic setting, it can be imagined that if every C H 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 C H bonds by developing palladium-catalyzed, site selective C H 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 C H functionalization, but streamline the synthesis of a variety of natural products with biological activity and expand upon methods to access highly valuable enantiopure materials.

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 PdII, RhIII, and RuII 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.

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 towards a silver free protocol for this reaction are also demonstrated.

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.

Contemporary organic chemists employ a broad range of catalytic and stoichiometric methods to construct molecules for applications in many fields, including material sciences1, pharmaceuticals2–5, agrochemicals, and sensors6. The potential utility of a synthetic method can be greatly reduced if it relies on the use of air- and/or moisture-sensitive reagents or catalysts. Furthermore, many synthetic chemistry laboratories have numerous containers of partially used reagents that have been spoiled by exposure to the ambient atmosphere. This is exceptionally wasteful from both an environmental and a cost perspective. In this manuscript, we report an encapsulation method through which air- and moisture-sensitive sensitive compounds can be rendered stable and stored on a laboratory bench top. We demonstrate this approach in three contexts, by describing single use capsules that contain all of the reagents (i.e., catalysts, ligands, and bases) necessary for palladium-catalyzed carbon–fluorine7–9, carbon–nitrogen10,11, and carbon–carbon12 bond forming reactions. The strategy described in this paper should be broadly applicable to a wide range of reagents and catalysts and should have the power to be transformative in preparative organic chemistry, particularly for inexperienced chemists. In addition, this approach will reduce the amount of tedious and time-consuming weighing procedures for the synthetic chemist performing these techniques on a large number of substrate combinations.

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.

Compounds that are sensitive to the components of air are difficult to use in chemical reactions, requiring conditions that are tedious to set up. A simple, practical solution to this problem has finally been devised. See Letter p.208 The chemical synthesis of many compounds for applications ranging from materials science to drug discovery rely on components that are sensitive to oxygen and water contained in the atmosphere, and many valuable chemical reagents spoil before they are fully consumed. Stephen Buchwald and colleagues report an encapsulation method that uses paraffin wax to render sensitive compound mixtures stable so that they can be stored on a laboratory bench top. The authors demonstrate this approach in single-use capsules that contain all of the reagents (catalysts, ligands, and bases) necessary for palladium-catalysed carbon–fluorine, carbon–nitrogen, and carbon–carbon bond forming reactions. The strategy described here should be broadly applicable to a wide range of reagents and catalysts, making many more synthetic processes readily available to non-specialist laboratories.