Palladium Catalyzed -C-H Functionalization of Masked Aromatic Aldehydes.

Palladium catalyzed -C-H functionalization enabled by transient mediators has the potential to extend the utility of directed C-H functionalization to remote positions. However, there have been no reports of palladium catalyzed 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 C-H functionalization of masked aromatic aldehydes.

Ligand-accelerated non-directed C-H functionalization of arenes.

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.

Ligand-Enabled Auxiliary-Free meta-C-H Arylation of Phenylacetic Acids.

The meta-C-H arylation of free phenylacetic acid was realized using 2-carbomethoxynorbornene (NBE-CO 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.

Ligand-Promoted meta-C-H Functionalization of Benzylamines.

Meta-C-H functionalization of benzylamines has been developed using a Pd /transient mediator strategy. Using 2-pyridone ligands and 2-carbomethoxynorbornene (NBE-CO 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.

Rh(III)-Catalyzed meta-C-H Olefination Directed by a Nitrile Template.

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.

Ligand-Enabled meta-Selective C-H Arylation of Nosyl-Protected Phenethylamines, Benzylamines, and 2-Aryl Anilines.

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.

Ligand Promoted meta-C-H Chlorination of Anilines and Phenols.

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.

Ligand-Promoted meta-C-H Amination and Alkynylation.

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.

A Simple and Versatile Amide Directing Group for C-H Functionalizations.

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.

Ligand-Promoted Meta-C-H Arylation of Anilines, Phenols, and Heterocycles.

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.

Monoselective o-C-H Functionalizations of Mandelic Acid and α-Phenylglycine.

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.

Unlocking nature's C-H bonds.

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.