1.1 Introduction to Pd-catalyzed directed C–H functionalization
The development of methods for the direct conversion of carbon–hydrogen bonds into carbon-oxygen, carbon-halogen, carbon-nitrogen, carbon-sulfur, and carbon-carbon bonds remains a critical challenge in organic chemistry. Mild and selective transformations of this type will undoubtedly find widespread application across the chemical field, including in the synthesis of pharmaceuticals, natural products, agrochemicals, polymers, and feedstock commodity chemicals. Traditional approaches for the formation of such functional groups rely on pre-functionalized starting materials for both reactivity and selectivity. However, the requirement for installing a functional group prior to the desired C–O, C–X, C–N, C–S, or C–C bond adds costly chemical steps to the overall construction of a molecule. As such, circumventing this issue will not only improve atom economy but also increase the overall efficiency of multi-step synthetic sequences.

Direct C–H bond functionalization reactions are limited by two fundamental challenges: (i) the inert nature of most carbon-hydrogen bonds and (ii) the requirement to control site selectivity in molecules that contain diverse C–H groups. A multitude of studies have addressed the first challenge by demonstrating that transition metals can react with C–H bonds to produce C–M bonds in a process known as “C–H activation”.1 The resulting C–M bonds are far more reactive than their C–H counterparts, and in many cases they can be converted to new functional groups under mild conditions.

The second major challenge is achieving selective functionalization of a single C–H bond within a complex molecule. While several different strategies have been employed to address this issue, the most common (and the subject of the current review) involves the use of substrates that contain coordinating ligands. These ligands (often termed “directing groups”) bind to the metal center and selectively deliver the catalyst to a proximal C–H bond. Many different transition metals, including Ru, Rh, Pt, and Pd, undergo stoichiometric ligand-directed C–H activation reactions (also known as cyclometalation).2,3 Furthermore, over the past 15 years, a variety of catalytic carbon-carbon bond-forming processes have been developed that involve cyclometalation as a key step.1b–d,4

The current review will focus specifically on ligand-directed C–H functionalization reactions catalyzed by palladium. Palladium complexes are particularly attractive catalysts for such transformations for several reasons. First, ligand-directed C–H functionalization at Pd centers can be used to install many different types of bonds, including carbon-oxygen, carbon-halogen, carbon-nitrogen, carbon-sulfur, and carbon-carbon linkages. Few other catalysts allow such diverse bond constructions,5,6,7 and this versatility is predominantly the result of two key features: (i) the compatibility of many PdII catalysts with oxidants and (ii) the ability to selectively functionalize cyclopalladated intermediates. Second, palladium participates in cyclometalation with a wide variety of directing groups, and, unlike many other transition metals, promotes C–H activation at both sp2 and sp3 C–H sites. Finally, the vast majority of Pd-catalyzed directed C–H functionalization reactions can be performed in the presence of ambient air and moisture, making them exceptionally practical for applications in organic synthesis.

While several accounts have described recent advances, this is the first comprehensive review encompassing the large body of work in this field over the past 5 years (2004–2009). Both synthetic applications and mechanistic aspects of these transformations are discussed where appropriate, and the review is organized on the basis of the type of bond being formed.

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Palladium-Catalyzed Ligand-Directed C−H Functionalization Reactions

Pick your Pd partners: A number of catalytic systems have been developed for palladium-catalyzed CH activation/CC bond formation. Recent studies concerning the palladium(II)-catalyzed coupling of CH bonds with organometallic reagents through a PdII/Pd0 catalytic cycle are discussed (see scheme), and the versatility and practicality of this new mode of catalysis are presented. Unaddressed questions and the potential for development in the field are also addressed.

In the past decade, palladium-catalyzed CH activation/CC bond-forming reactions have emerged as promising new catalytic transformations; however, development in this field is still at an early stage compared to the state of the art in cross-coupling reactions using aryl and alkyl halides. This Review begins with a brief introduction of four extensively investigated modes of catalysis for forming CC bonds from CH bonds: PdII/Pd0, PdII/PdIV, Pd0/PdII/PdIV, and Pd0/PdII catalysis. A more detailed discussion is then directed towards the recent development of palladium(II)-catalyzed coupling of CH bonds with organometallic reagents through a PdII/Pd0 catalytic cycle. Despite the progress made to date, improving the versatility and practicality of this new reaction remains a tremendous challenge.

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Palladium(II)-catalyzed C-H activation/C-C cross-coupling reactions: versatility and practicality.

Catalytic dehydrogenative cross-coupling: forming carbon-carbon bonds by oxidizing two carbon-hydrogen bonds

Functionalizing traditionally inert carbon–hydrogen bonds represents a powerful transformation in organic synthesis, providing new entries to valuable structural motifs and improving the overall synthetic efficiency. C–H bond activation, however, often necessitates harsh reaction conditions that result in functional group incompatibilities and limited substrate scope. An understanding of the reaction mechanism and rational design of experimental conditions have led to significant improvement in both selectivity and applicability. This critical review summarizes and discusses endeavours towards the development of mild C–H activation methods and wishes to trigger more research towards this goal. In addition, we examine select examples in complex natural product synthesis to demonstrate the synthetic utility of mild C–H functionalization (84 references).

Towards mild metal-catalyzed C–H bond activation

https://cyberleninka.org/article/n/132565.pdf

Discovery and resupply of pharmacologically active plant-derived natural products: A review.

Synthetic photochemistry carried out in classic batch reactors has, for over half a century, proved to be a powerful but under-utilised technique in general organic synthesis. Recent developments in flow photochemistry have the potential to allow this technique to be applied in a more mainstream setting. This review highlights the use of flow reactors in organic photochemistry, allowing a comparison of the various reactor types to be made.

https://www.beilstein-journals.org/bjoc/content/pdf/1860-5397-8-229.pdf

Flow photochemistry: Old light through new windows

Compact flow reactors have been constructed and optimized to perform continuous organic photochemistry on a large scale. The reactors were constructed from commercially available or customized imme...

A practical flow reactor for continuous organic photochemistry.

A Pd-catalyzed intermolecular 1,2-carboamination route to indolines from N-aryl ureas and 1,3-dienes that proceeds under mild conditions in relatively nonacidic media, is presented. The in situ generation, or preformation, of a palladium tosylate emerges as a key parameter in gaining the requisite reactivity for the C−H insertion/carbopalladation/nucleophilic displacement process.

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Distinct reactivity of Pd(OTs)2: the intermolecular Pd(II)-catalyzed 1,2-carboamination of dienes.

Pd and CO--ureally got me! The title reaction proceeds efficiently at 18 degrees C under CO (1 atm) with 5 % [Pd(OTs)(2)(MeCN)(2)] as precatalyst. Depending on the solvents used, either anthranilates or cyclic imides can be obtained in high yields (see picture, BQ = benzoquinone, Ts = 4-toluenesulfonyl).

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Room‐Temperature Palladium‐Catalyzed C ? H Activation: ortho‐Carbonylation of Aniline Derivatives

A Pd(II) chloride precatalyst, in the presence of 1 equiv of benzoquinone, effects highly efficient, regioselective 1,2-diamination of 1,3-dienes using dialkyl ureas under mild conditions. There is no requirement for a large excess of diene.

Kevin I. Booker-Milburn

Papers

Flow photochemistry: Old light through new windows

A practical flow reactor for continuous organic photochemistry.

Distinct reactivity of Pd(OTs)2: the intermolecular Pd(II)-catalyzed 1,2-carboamination of dienes.

Room‐Temperature Palladium‐Catalyzed C ? H Activation: ortho‐Carbonylation of Aniline Derivatives

Pd(II)-Catalyzed Intermolecular 1,2-Diamination of Conjugated Dienes