Concerted metallation deprotonation

Abstract Azines, diazines or thiazole (V-oxides are highly reactive substrates in palladium-catalyzed direct arylation reaction. For these reactions, the results are inconsistent with an SEAr reaction pathway and may best fit with a concerted metalation-deprotonation-like (CMD) mechanism. 

Ongoing research in our group and by others [62-65] on the mechanism of palladium-catalyzed direct arylation has led to the advancement of a second mode of C-H bond cleavage where a Wheland-like intermediate is not involved in the reaction pathway (Scheme 4). This pathway, which we have termed a concerted metalation-deprotonation (CMD) mechanism, appears less dependent on arene... 

Scheme 4 A prototypical concerted metalation-deprotonation (CMD) direct arylation mechanism...

Gorelsky SI, Lapointe D, Fagnou K (2008) Analysis of the concerted metalation-deprotonation mechanism in palladium-catalyzed direct arylation across a broad range of aromatic substrates. J Am Chem Soc 130 10848-10849... 

A significantly more active catalytic system was recently reported, with a ruthenium complex generated from carboxylic acid 75. This allowed for direct arylations to occur also in apolar solvents likely via a concerted metalation-deprotonation mechanism (CMD) and set the stage for the use of aryl bromides, chlorides, and tosylates as electrophilic substrates (Scheme 9.26) [64],... 

Our initial work in the oxidative aryiation of heteroarenes was an example of the discovery of new chemical territory. However, we sought to not just discover this new reactivity, but to understand it. Consequently, both experimental and computational studies were performed to elucidate the mechanism of the oxidative indole arylations. Both sets of data indicate a concerted metalation-deprotonation mechanism (CMD) for the palladation of both the... 

Then the C—H bond eleavage may occur via concerted metallation deprotonation (CMD) to generate the Pd" intermediate. After the following reductive elimination, the Pd catalyst is regenerated. The overall redox process of the Pd species does not require an external stoichiometric oxidant, which is friendly to the environment. 

In a foUow-up paper, the group disclosed a possible mechanism for direct arylation based on a concerted metalation—deprotonation pathway (Scheme 11) (2010JOC8180). Kinetic experiments revealed a zero order... 

The results indicate that the rate- and regio-determining step involves concerted metalation-deprotonation, as shown in (23), to give an aryl palladium intermediate. This is followed by substitution of the pyridine ligand, L, by the alkene and insertion of the alkene double bond into the palladium—aryl bond. The absence of ortho-substituted product results from steric repulsion between the ring substituent,... 

DFT calculations have been reported of the copper-catalysed reaction of A-methyl indoles with amides, which result in amidation at the 2-position. The results show that a concerted metalation—deprotonation pathway does not explain the observed regioselectivity. Instead, a four-centre reductive elimination involving the transition state (80) is proposed. The reaction is likely to be completed by proton transfer from the amidated carbon atom to the butoxy ligand. Copper-catalysed reaction of azoles or polyfluoroarenes with sulfoximines may produce A-aryl sulfoximines. Owing to the mild reaction conditions, enantiopurity in the starting sulfoximine is retained in products such as (81). 

The mechanism of direct arylation has been studied experimentally and computationally and possible pathways include electrophilic aromatic substitution, Heck-type coupling and concerted metalation-deprotonation (CMD). The reaction pathway is dependent on the substrate and the catalytic system employed,however, most electron-rich (hetero)arenes seem to follow a base-assisted CMD pathway. Two catalytic cycles for the coupling of bromo-benzene and thiophene are shown in Schemes 19.5 and 19.6. Scheme 19.5 depicts a carboxylate-mediated process where C-H activation occurs... 

The nature of the C-H activation step has been widely discussed in several studies. There are three accepted pathways for the mechanism of the C-H cleavage oxidative addition, electrophilic substitution, and concerted metallation-deprotonation (CMD). ° The reaction of [RuCl2(arene)]2 complexes with heteroarenes or benzylamines in the presence of a base has been shown to favour the formation of stable ruthenacycles. This evidence confirmed the crucial role of the base in the... 

In the next section we will discuss another important mechanistic pathway that has been proposed to be operating in several C-H bond functionalization reactions i.e. a c-bond metathesis (also called as Concerted Metallation Deprotonation (CMD). 

Concerted metalation deprotonation (CMD) (o-bond metathesis of C-H bond)... 

Sigma bond metathesis is another important pathway that could be followed for the C-H bond activation of (hetero)arenes. Recently, the term a-bond metathesis has undergone a radical change and has been rather appropriately coined Concerted Metallation Deprotonation (CMD) pathway," sometime also known as internal electrophihc substitution or ambiphilic metal-ligand activation. ... 

Concerted metalation deprotonation (CMD)/ambiphilic metal ligand activation (AMLA) lA.CMD through 6-membered transition states... 

Concerted metalation deprotonation Protecting-directing groups Sigma bond metathesis... 

A more appealing strategy for arene C—H functionalizations involves the use of simple benzene derivatives lacking DGs. The overall pathway for such transformations entails metal mediated C—H activation to afford the metal-aiyl intermediate Ai M followed by subsequent functionalization of Ai M to release the desired product (Scheme 24.1). The C—H activation step can proceed via oxidative addition, sigma bond metathesis, or concerted metalation deprotonation pathway. The exact mechanism of C—H cleavage is dependent on the nature of the metal and the ancUlaiy ligands [1,3]. 

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