Synthesis of Phenolic Compounds via Palladium Catalyzed C−H Functionalization of Arenes

Phenol and its derivatives are extremely useful compounds in organic synthesis, medicinal chemistry and material sciences. The synthesis of phenols involving selective construction of the C?O bond at a C?H bond of arenes using transition‐metal catalysis represents the most appealing strategy. Indeed, active research is currently going on for the synthesis of valuable phenolic compounds using a transition‐metal‐catalyzed C?H functionalization strategy. This short review summarizes recent advances on palladium‐catalyzed C?O bond forming reactions that enable direct access to phenolic compounds. These catalytic reactions proceed either via C?H esterification with trifluoroacetic acid/trifluoroacetic anhydride followed by in situ hydrolysis of the ester or via direct C?H hydroxylation. A brief analysis of substrate scope and limitation, reaction mechanism as well as synthetic utility of these reactions has been included.     

Increasing Catalyst Efficiency in C−H Activation Catalysis

C?H activation reactions with high catalyst turnover numbers are still very rare in the literature and 10 mol % is a common catalyst loading in this field. We offer a representative overview of efficient C?H activation catalysis to highlight this neglected aspect of catalysis development and inspire future effort towards more efficient C?H activation. Examples ranging from palladium catalysis, Cp*Rh^III‐ and Cp*Co^III‐catalysis, the C?H borylation and silylation to methane C?H activation are presented. In these reactions, up to tens of thousands of catalyst turnovers have been observed.     

Copper‐Catalyzed Insertion into Heteroatom–Hydrogen Bonds with Trifluorodiazoalkanes

Copper‐catalyzed Si?H, B?H, P?H, S?H, and N?H insertion reactions of 2,2,2‐trifluoro‐1‐diazoethane and 1‐aryl 2,2,2‐trifluorodiazoethanes generated a large number of new fluorine‐containing chemical entities for medicinal chemists. With selected Si?H and B?H insertion reactions, we demonstrate successful extension to asymmetric catalysis.     

Regioselective Arene C−H Alkylation Enabled by Organic Photoredox Catalysis

Expanding the toolbox of C?H functionalization reactions applicable to the late‐stage modification of complex molecules is of interest in medicinal chemistry, wherein the preparation of structural variants of known pharmacophores is a key strategy for drug development. One manifold for the functionalization of aromatic molecules utilizes diazo compounds and a transition‐metal catalyst to generate a metallocarbene species, which is capable of direct insertion into an aromatic C?H bond. However, these high‐energy intermediates can often require directing groups or a large excess of substrate to achieve efficient and selective reactivity. Herein, we report that arene cation radicals generated by organic photoredox catalysis engage in formal C?H functionalization reactions with diazoacetate derivatives, furnishing sp²–sp³ coupled products with moderate‐to‐good regioselectivity. In contrast to previous methods utilizing metallocarbene intermediates, this transformation does not proceed via a carbene intermediate, nor does it require the presence of a transition‐metal catalyst.     

Molecular Radical Chain Initiators for Ambient‐ to Low‐Temperature Applications

An overview of methods for the initiation of radical chain reactions by specific initiator compounds, which generate radicals, is given. These can be utilized to initiate any kind of radical chain reaction by transforming substrates into the desired radical intermediates. Azo initiators, peroxides, nitroxides, trialkylboranes, dialkyl zinc compounds, and type I photoinitiators are discussed, as well as methods of redox‐ and sonochemical initiation. Methods of direct radical formation from the substrates, such as photoredox catalysis or high‐energy irradiation, are not included. The focus of this review lies on rather “low” temperatures in the range of 50 °C down to ?78 °C, which can be useful to achieve more selective reactions. Illustrative applications of such radical chain initiators in a variety of reactions are discussed, including stereoselective ones and polymerizations.     

Advances in Copper‐Catalyzed C?C Coupling Reactions and Related Domino Reactions Based on Active Methylene Compounds

Active methylene compounds are a major class of reaction partners for C? C bond formation with sp² C? X (X=halide) fragments. As one of the most‐classical versions of the Ullmann‐type coupling reaction, activated‐methylene‐based C? C coupling reactions have been efficiently employed in a large number of syntheses. Although this type of reaction has long relied on noble‐metal catalysis, the renaissance of copper catalysis at the end of last century has led to dramatic developments in Ullmann C? C coupling reactions. Owing to its low cost, abundance, as well as excellent catalytic activity, the exceptional atom economy of copper catalysis is gaining widespread attention in various organic synthesis. This review summarizes the advances in copper‐catalyzed intermolecular and intramolecular C? C coupling reactions that use activated methylene species as well as in tandem reactions that are initiated by this transformation.     

Syntheses with Radicals—C?C Bond Formation via Organotin and Organomercury Compounds [New Synthetic Methods (52)]

C? C bond formation is one of the most important synthetic steps in the construction of organic molecules. In the last few years it has been increasingly achieved by radical addition to alkenes. In such reactions the adduct radicals have to be trapped by an donor subsequent to the C? C bond formation in order to prevent polymerization. This task can be accomplished with organotin and organomercury hydrides, the use of which has led to new synthetic methods. The occurrence of radical chain reactions in which reactions take place between radicals and nonradicals is decisive for the success of the synthesis. In these cases small amounts of radical initiators suffice and numerous functional groups may be used in the C? C bond-forming reactions. The yields and selectivities of these radical reactions are often very high.     

Revised Role of Selectfluor in Homogeneous Au‐Catalyzed Oxidative CO Bond Formations

The pairing of transition metal catalysis with the reagent Selectfluor (F‐TEDA–BF₄) has attracted considerable attention due to its utility in myriad C?C and C?heteroatom bond‐forming reactions. However, little mechanistic information is available for Selectfluor‐mediated transition metal‐catalyzed reactions and controversy surrounds the precise role of Selectfluor in these processes. We present herein a systematic investigation of homogeneous Au‐catalyzed oxidative C?O bond‐forming reactions using density functional theory calculations. Currently, Selectfluor is thought to serve as an external oxidant in Au^I/Au^III catalysis. However, our investigations suggest that these reactions follow a newly proposed mechanism in which Selectfluor functions as an electrophilic fluorinating reagent involved in a fluorination/defluorination cycle. We have also explored Selectfluor‐mediated gold‐catalyzed homocoupling reactions, which, when cyclopropyl propargylbenzoate is used as a substrate, lead to an unexpected byproduct.     

Silylium ion-catalyzed challenging Diels-Alder reactions: the danger of hidden proton catalysis with strong Lewis acids

The pronounced Lewis acidity of tricoordinate silicon cations brings about unusual reactivity in Lewis acid catalysis. The downside of catalysis with strong Lewis acids is, though, that these do have the potential to mediate the formation of protons by various mechanisms, and the thus released Br?nsted acid might even outcompete the Lewis acid as the true catalyst. That is an often ignored point. One way of eliminating a hidden proton-catalyzed pathway is to add a proton scavenger. The low-temperature Diels-Alder reactions catalyzed by our ferrocene-stabilized silicon cation are such a case where the possibility of proton catalysis must be meticulously examined. Addition of the common hindered base 2,6-di-tert-butylpyridine resulted, however, in slow decomposition along with formation of the corresponding pyridinium ion. Quantitative deprotonation of the silicon cation was observed with more basic (Mes)(3)P to yield the phosphonium ion. A deuterium-labeling experiment verified that the proton is abstracted from the ferrocene backbone. A reasonable mechanism of the proton formation is proposed on the basis of quantum-chemical calculations. This is, admittedly, a particular case but suggests that the use of proton scavengers must be carefully scrutinized, as proton formation might be provoked rather than prevented. Proton-catalyzed Diels-Alder reactions are not well-documented in the literature, and a representative survey employing TfOH is included here. The outcome of these catalyses is compared with our silylium ion-catalyzed Diels-Alder reactions, thereby clearly corroborating that hidden Br?nsted acid catalysis is not operating with our Lewis acid. Several simple-looking but challenging Diels-Alder reactions with exceptionally rare dienophile/enophile combinations are reported. Another indication is obtained from the chemoselectivity of the catalyses. The silylium ion-catalyzed Diels-Alder reaction is general with regard to the oxidation level of the α,β-unsaturated dienophile (carbonyl and carboxyl), whereas proton catalysis is limited to carbonyl compounds.     

Catalysis by Molecular Metal Clusters

Molecular metal clusters form a very large and diverse family. They present the opportunity of modeling the intermediates involved in surface mediated catalytic reactions, of providing a source of very reactive mononuclear metal fragments, and of effecting catalytic cycles in which the cluster remains intact. The last mentioned aspect is the subject of this review article. The state-of-the-art of cluster catalysis is critically analyzed. The possibilities offered by molecular metal catalysts of performing catalytic reactions at multimetal atom sites are also discussed.     

Chiral Counteranion Strategy for Asymmetric Oxidative C(sp3)H/C(sp3)H Coupling: Enantioselective α‐Allylation of Aldehydes with Terminal Alkenes

The first enantioselective α‐allylation of aldehydes with terminal alkenes has been realized by combining asymmetric counteranion catalysis and palladium‐catalyzed allylic C? H activation. This method can tolerate a wide scope of α‐branched aromatic aldehydes and terminal alkenes, thus affording allylation products in high yields and with good to excellent levels of enantioselectivity. Importantly, the findings suggest a new strategy for the future creation of enantioselective C? H/C? H coupling reactions.     

Methandiide as a Non‐Innocent Ligand in Carbene Complexes: From the Electronic Structure to Bond Activation Reactions and Cooperative Catalysis

The synthesis of a ruthenium carbene complex based on a sulfonyl‐substituted methandiide and its application in bond activation reactions and cooperative catalysis is reported. In the complex, the metal–carbon interaction can be tuned between a Ru?C single bond with additional electrostatic interactions and a Ru?C double bond, thus allowing the control of the stability and reactivity of the complex. Hence, activation of polar and non‐polar bonds (O?H, H?H) as well as dehydrogenation reactions become possible. In these reactions the carbene acts as a non‐innocent ligand supporting the bond activation as nucleophilic center in the 1,2‐addition across the metal–carbon double bond. This metal–ligand cooperativity can be applied in the catalytic transfer hydrogenation for the reduction of ketones. This concept opens new ways for the application of carbene complexes in catalysis.     

Reaction Mechanisms in Heterogeneous Catalysis; C?H Activation as a Case Study

Heterogeneous catalysis is changing from an empirical art to an exact science. The various methods for the analysis of solids and surfaces, constantly refined by materials science and surface science, seem to be almost unlimited. The increasing availability of atomic resolution microscopy as well as synchrotron radiation allows the characterization of catalyst particles, surface structures, surface processes and surface intermediates. We have learned to determine the surface structure sensitivity of catalytic reactions. Thermodynamic and kinetic data of catalytic reactions are now determined routinely. Isotopic exchange and labeling experiments provide information about reactant-catalyst interactions. How much have we learned through these techniques about the nature or mechanism of heterogeneously catalyzed reactions? The following article attempts to summarize the progress and the problems encountered in mechanistic studies of C? H bond formation and activation in a hydrogen atmosphere as an example for the present state of the understanding of reaction mechanisms in heterogeneous catalysis.     

New progress in theoretical studies on palladium-catalyzed C−C bond-forming reaction mechanisms

This review reports a series of mechanistic studies on Pd-catalyzed C-C cross-coupling reactions via density functional theory(DFT) calculations.A brief introduction of fundamental steps involved in these reactions is given,including oxidative addition,transmetallation and reductive elimination.We aim to provide an important review of recent progress on theoretical studies of palladium-catalyzed carbon-carbon cross-coupling reactions,including the C-C bond formation via C-H bond activation,decarboxylation,Pd(Ⅱ)/Pd(Ⅳ) catalytic cycle and double palladiums catalysis.     

Catalysis of Radical Reactions: A Radical Chemistry Perspective

The area of catalysis of radical reactions has recently flourished. Various reaction conditions have been discovered and explained in terms of catalytic cycles. These cycles rarely stand alone as unique paths from substrates to products. Instead, most radical reactions have innate chains which form products without any catalyst. How do we know if a species added in “catalytic amounts” is a catalyst, an initiator, or something else? Herein we critically address both catalyst‐free and catalytic radical reactions through the lens of radical chemistry. Basic principles of kinetics and thermodynamics are used to address problems of initiation, propagation, and inhibition of radical chains. The catalysis of radical reactions differs from other areas of catalysis. Whereas efficient innate chain reactions are difficult to catalyze because individual steps are fast, both inefficient chain processes and non‐chain processes afford diverse opportunities for catalysis, as illustrated with selected examples.     

Photoredox‐Catalyzed Reductive Coupling of Aldehydes,Ketones, and Imines with Visible Light

Ketyl radical and amino radical anions, valuable reactive intermediates for C? C bond‐forming reactions, are accessible through a C?O/C?NR umpolung. However, their utilization in catalysis remains largely underdeveloped owing to the high reduction potential of carbonyl compounds and imines. In the context of photoredox catalysis, tertiary amines are commonly employed as sacrificial co‐reducing agents. Herein, an additional role of the amine is proposed, in which it is essential for the organocatalytic substrate activation. The combination of photoredox catalysis and carbonyl/imine activation enables the reductive coupling of aldehydes, ketones, and imines under mild reaction conditions.     

Super Brønsted acid catalysis

Br?nsted acid catalysis has emerged as a new class of catalysis in modern organic synthesis. However, in order to make the utility of the Br?nsted acid catalysis as broad as the well-developed Lewis acid catalysis, it is desirable to develop Br?nsted acids demonstrating both high reactivities and selectivities. In this feature article, we will present our achievement in the design and development of strong Br?nsted acids and their application to organic reactions. Furthermore, we will describe the Tf(2)NH-catalyzed Mukaiyama aldol reaction of super silyl enol ethers. We also will highlight the differences in reactivity and chemo- and stereo-selectivity between Br?nsted and Lewis acid catalysis.     

Oxidative Coupling of Aromatic Substrates with Alkynes and Alkenes under Rhodium Catalysis

Aromatic substrates with oxygen‐ and nitrogen‐containing substituents undergo oxidative coupling with alkynes and alkenes under rhodium catalysis through regioselective C? H bond cleavage. Coordination of the substituents to the rhodium center is the key to activate the C? H bonds effectively. Various fused‐ring systems can be constructed through these reactions.     

Enantioselective S−H Insertion Reactions of α‐Carbonyl Sulfoxonium Ylides

The first example of enantioselective S?H insertion reactions of sulfoxonium ylides is reported. Under the influence of thiourea catalysis, excellent levels of enantiocontrol (up to 95 % ee) and yields (up to 97 %) are achieved for 31 examples in S?H insertion reactions of aryl thiols and α‐carbonyl sulfoxonium ylides.     

Combining Rhodium and Photoredox Catalysis for CH Functionalizations of Arenes: Oxidative Heck Reactions with Visible Light

Direct, oxidative metal‐catalyzed C? H functionalizations of arenes are important in synthetic organic chemistry. Often, (over‐)stoichoimetric amounts of organic or inorganic oxidants have to be used in these reactions. The combination of rhodium and photoredox catalysis with visible light allows the direct C? H olefination of arenes. Small amounts (1 mol %) of a photoredox catalyst resulted in the efficient C? H functionalization of a broad range of substrates under mild conditions.