Concerted metalation-deprotonation 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... 

Potavathri S, Pereira KC, Gorelsky SI, Pike A, LeBris AP, DeBoef B (2010) Regioselective oxidative arylation of indoles bearing W-alkyl protecting groups dual C-H functionalization via a concerted metallation-deprotonation mechanism. J Am Chem Soc 132 14676-14681... 

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...

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 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... 

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]. 

Finally, C—H bond activations that proceed through organometallic intermediates with M—C bonds are common mechanistic pathways toward C—H functionalizations. Several distinct mechanisms for C—H cleavage (o-bond metathesis oxidative addition concerted metalation deprotonation through 4- or 6-membered transition states) have been elucidated for this step. The exact pathway of C—H bond activation typically depends on the identity of the metal, its oxidation state, and the ancillary ligands. 

Most of the mechanisms for heteroaromatic C—H bond activation by a transition-metal catalyst fall into one of these four categories (i) electrophilic aromatic metala-tion, (ii) carboxylate-ligand-promoted concerted metalation-deprotonation (CMD), (iii) base-assisted metalation and (iv) oxidative addition of C—H to the metal center. The type of mechanism operating in the cleavage of the C—bond depends on the electronics of the heterocycle (and therefore its substituents) and the reaction conditions being employed. 

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