The cleavage of aromatic CH bonds promoted by a metal and an intramolecular base has been described over 50 years ago. Herein, discussion of selected mechanistic studies of this transformation will be presented. The basic ligand on the metal was proven to play a pivotal role in the CH bond cleavage step and evidence of a single operative concerted metallation deprotonation mechanism unifies the different mechanistic studies.

The concerted metalation-deprotonation mechanism predicts relative reactivity and regioselectivity for a diverse set of arenes spanning the entire spectrum of known palladium-catalyzed direct arylation coupling partners. An analysis following an active strain model provides a more complete portrayal of the important arene/catalyst parameters leading to a successful coupling. The breadth of arenes whose reactivity can be predicted by the CMD mechanism indicates that it may be far more widespread than previously imagined.

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The development of new reactions capable of catalytically transforming the inert C-H bonds of organic molecules into useful functional groups is an important and very active area of research. 1 With this process, problems associated with low reactivity and selectivity are compounded by an only emerging appreciation of the mechanistic possibilities. As a consequence, the discovery of new catalytic reactivity can be of tremendous impact. An illustrative class of C-H functionalization that is limited by mechanistic understanding is direct arylation. 2,3 With these reactions, the most common mechanism of C-H bond cleavage is electrophilic aromatic substitution (S E Ar) involving reaction of an electrophilic metal catalyst with an electron-rich, nucleophilic aromatic ring. 4,5 This pathway is fundamentally limiting since the vast majority of aromatic compounds are not sufficiently nucleophilic. 6 For example, simple and electron-deficient arenes have never been successfully employed in catalytic direct arylation (eq 1) except when a basic directing group can enable the formation of a metallacycle. 7,8 New mechanistic insights that overcome these constraints and enable catalytic direct arylation to be performed with currently inaccessible arene classes would not only be of tremendous importance in biaryl synthesis but would also be transformative in the rational design of other types of catalytic arene functionalization.Herein, we describe intermolecular direct arylation reactions of electron-deficient benzenes and associated computational studies indicating that metallacyclic intermediates are not involved. Underlying these new transformations is a mechanism that actually favors reaction with electron-deficient, C-H acidic benzeness constituting a complete inVersion of reactivity compared to the S E Ar pathway. Computational studies reveal the key C-H bond functionalization step occurs via a concerted arene metalation and carbon-hydrogen bond cleaving process, the accessibility of which depends directly on the acidity of the C-H bond being cleaved. These reactions are scalable, can employ a nearly equimolar ratio of the two benzene cross-coupling components, and produce perfluorobiphenyl products that have demonstrated importance in medicinal chemistry, 9 electron-transport devices, 10 organic light emitting diodes, 11 sensitizers for the photo-splitting of water, 12 and as elements in the rational design of liquid crystals. 13 It is anticipated that these new reactions will begin to replace the use of fluorobenzene organometallics in the synthesis of fluorobiaryl molecules and that the new reactivity should facilitate the design of other catalytic C-H bond functionalizations.As a starting point, we chose to examine the direct arylation of pentafluorobenzene since this substrate would not react via a S E Artype process. Reaction screens were performed with 4-bromotoluene as the second coupling partner, and efforts were made to achieve conditions that were operationally simple. We were excited to find that excellent ...

Directing groups that can act as internal oxidants have recently been shown to be beneficial in metal-catalyzed heterocycle syntheses that undergo C-H functionalization. Pursuant to the rhodium(III)-catalyzed redox-neutral isoquinolone synthesis that we recently reported, we present in this article the development of a more reactive internal oxidant/directing group that can promote the formation of a wide variety of isoquinolones at room temperature while employing low catalyst loadings (0.5 mol %). In contrast to previously reported oxidative rhodium(III)-catalyzed heterocycle syntheses, the new conditions allow for the first time the use of terminal alkynes. Also, it is shown that the use of alkenes, including ethylene, instead of alkynes leads to the room temperature formation of 3,4-dihydroisoquinolones. Mechanistic investigations of this new system point to a change in the turnover limiting step of the catalytic cycle relative to the previously reported conditions. Concerted metalation-deprotonation (CMD) is now proposed to be the turnover limiting step. In addition, DFT calculations conducted on this system agree with a stepwise C-N bond reductive elimination/N-O bond oxidative addition mechanism to afford the desired heterocycle. Concepts highlighted by the calculations were found to be consistent with experimental results.

A catalyst for the intramolecular direct arylation of a broad range of simple and heterocyclic arenes with aryl iodides, bromides, and chlorides has been developed. These reactions occur in excellent yield and are highly selective. Studies with aryl iodides substrates revealed that catalyst poisoning occurs due to the accumulation of iodide in the reaction media. This can be overcome by the addition of silver salts which also permits these reactions to occur at lower temperature. The utility of the methodology is illustrated by a rapid synthesis of a carbazole natural product and by the synthesis of sterically encumbered tetra-ortho-substituted biaryls via ring-opening reactions of the direct arylation products. Mechanistic investigations have provided insight into the catalyst's mode of action and show the presence of a kinetically significant C-H bond cleavage in palladium-catalyzed direct arylation of simple arenes. Knowledge garnered from these studies has led to the development of new intermolecular arylation reactions with previously inaccessible arenes, opening the door for the development of other new direct arylation processes.

Among the most common ligands found on transition metal catalysts are halide ions. Of the commercially available catalysts or pre‐catalysts, most are halo–metal complexes. In recent years, manipulation of this metal‐halide functionality has revealed that this can be used as a highly valuable method of tuning the reactivity of the complex. Variation of the halide ligand will usually not alter the nature of the system to the extent that it becomes unreactive but will impart sufficiently large changes that differences in reactivity or selectivity occur. These differences are a product of the steric and electronic properties of the halide ligand which has the ability to donate electron density to the metal occurs in a predictable manner. Despite the common perception in asymmetric catalysis that halide ligands are of secondary importance compared to chiral ligands, halide ligands have been found to exert dramatic effects on the enantioselectivity of asymmetric transformations. While the mechanism of action is known for relatively few of the cases, many intriguing and potentially synthetically useful trends are apparent. This review discusses the physical properties of the halides and their effects on stoichiometric and catalytic transition metal processes. The metal‐halide moiety thus emerges as a tunable functionality on the transition metal catalyst that can be used in the development of new catalytic systems.

A comprehensive understanding of the C-H bond cleavage step by the concerted metalation-deprotonation (CMD) pathway is important in further development of cross-coupling reactions using different catalysts. Distortion-interaction analysis of the C-H bond cleavage over a wide range of (hetero)aromatics has been performed in an attempt to quantify the various contributions to the CMD transition state (TS). The (hetero)aromatics evaluated were divided in different categories to allow an easier understanding of their reactivity and to quantify activation characteristics of different arene substituents. The CMD pathway to the C-H bond cleavage for different classes of arenes is also presented, including the formation of pre-CMD intermediates and the analysis of bonding interactions in TS structures. The effects of remote C2 substituents on the reactivity of thiophenes were evaluated computationally and were corroborated experimentally with competition studies. We show that nucleophilicity of thiophenes, evaluated by Hammett σ(p) parameters, correlates with each of the distortion-interaction parameters. In the final part of this manuscript, we set the initial equations that can assist in the development of predictive guidelines for the functionalization of C-H bonds catalyzed by transition metal catalysts.