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

It is difficult to imagine organic chemistry without organo-halogen compounds and the molecular halogens needed for their preparation. The halogens have very different reactivity, with iodine usually requiring some form of activation, while others are reactive and hazardous chemicals. To avoid their use, various modified reagents have been discovered (N-bromo- and N-chlorosuccinimide, Selectfluor..), but halogens are used to prepare these reagents and when they are used the atom economy is poor. A better approach, which is based on biomimetric research on oxidative halogenation in nature, consists of generating the halogenating reagent in situ under acidic conditions from a halide salt. The result of such a reaction has been halogenation with 100 % halogen atom economy. Suitable oxidants for the oxidation of halides are hydrogen peroxide and oxygen.

Oxidative Halogenation with "Green" Oxidants: Oxygen and Hydrogen Peroxide

Structurally dynamic polydisulfide networks that inherently exhibit both shape-memory and healable properties have been synthesized. These materials are semicrystalline, covalently cross-linked network polymers and as such exhibit thermal shape-memory properties. Upon heating above its melting temperature (Tm) films of the material can be deformed by a force. Subsequent cooling and removal of the force result in the material being “fixed” in this strained temporary shape through a combination of crystallinity and covalent cross-links until it is exposed to temperatures above the Tm at which point it recovers to its remembered processed shape. The incorporation of disulfide bonds, which become dynamic/reversible upon exposure to light or elevated temperatures, into these networks results in them being structurally dynamic upon exposure to the appropriate stimulus. Thus, by activating this disulfide exchange, the network reorganizes, and the material can flow and exhibit healable properties. Furthermore, ex...

Inherently Photohealable and Thermal Shape-Memory Polydisulfide Networks

The introduction of an O-acyl group at the α-position of carbonyl compounds is smoothly achieved using tetrabutylammonium iodide catalyst in the presence of hydrogen peroxide or tert-butyl hydroperoxide.

In situ generated (hypo)iodite catalysts for the direct α-oxyacylation of carbonyl compounds with carboxylic acids.

While natural and synthetic N-nucleosides are vulnerable to enzymatic and acid-catalyzed hydrolysis of the nucleosidic bond, their C-analogues are much more stable. Several C-nucleosides are naturally occurring compounds, e.g., pseudouridine (isolated from the yeast t-RNA) and showdomycin (an antibiotic). Development of novel synthetic methodologies allowed the preparation of a large variety of synthetic analogues, which found numerous applications in medicinal chemistry and chemical biology. Most important biologically active C-nucleosides are the inhibitors of purine nucleosides phosphorylase or IMP dehydrogenase. A number of artificial aryl-C-nucleosides capable of π-stacking are being vigorously investigated as building blocks in chemical biology. In the past few years, several Artificial Expanded Genetic Information Systems (AEGIS)1 have been successfully developed as prime examples of synthetic biology, a newly emerging interdisciplinary area, with the ultimate goal to design systems where high-level behaviors of the living matter are mimicked by artificial chemical systems.2,3

C-nucleosides: synthetic strategies and biological applications.

Thiols were effectively oxidized into disulfides by reacting with hydrogen peroxide in the presence of a catalytic amount of iodide ion or iodine.

A Mild and Environmentally Benign Oxidation of Thiols to Disulfides

Thiols were converted into disulfide by the aerobic oxidation catalyzed by trichlorooxyvanadium in the presence of molecular sieves 3A.

Aerobic oxidation of thiols to disulfides catalyzed by trichlorooxyvanadium.

Active methylene and methyne compounds can bechemoselectively brominated in high yields using potassiumbromide, hydrochloric acid, and hydrogen peroxide at room temper-ature. Key words: halogenation, halaides, green chemistry, bromination,active methylene compounds Halogenated active methylene and methyne compoundsare very important synthetic intermediates for the nucleo-philic substitutions in synthetic organic chemistry. Theclassical methods of halogenation of active methylene andmethyne compounds 1 are the reaction with bromine 1 orsulfuryl chloride, 2 however, they suffer from drawbackssuch as toxicity of the reagents, generation of acidicgasses after the reaction, or overhalogenation of thearomatic rings in 1 . Although a number of new methodsof this transformation have previously been developed,most of them have severe disadvantages such as theproduction of undesirable waste. 3–5 Khan and co-workers recently developed chemoselectivebromination of active methylene compounds by employ-ing the vanadium pentoxide catalyzed (V

Chemoselective Bromination of Active Methylene and Methyne Compounds by Potassium Bromide, Hydrochloric Acid and Hydrogen Peroxide

Reaction of tertiary cyclopropyl silyl ethers with diethylaminosulfur trifluoride: the effects of substituents on the cleavage of the cyclopropane ring

Masayuki Kirihara

Papers

A Mild and Environmentally Benign Oxidation of Thiols to Disulfides

Aerobic oxidation of thiols to disulfides catalyzed by trichlorooxyvanadium.

Chemoselective Bromination of Active Methylene and Methyne Compounds by Potassium Bromide, Hydrochloric Acid and Hydrogen Peroxide

Reaction of tertiary cyclopropyl silyl ethers with diethylaminosulfur trifluoride: the effects of substituents on the cleavage of the cyclopropane ring

Synthesis and characterization of a DNA analogue stabilized by mercapto C-nucleoside induced disulfide bonding.