Concerted metalation deprotonation CMD

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...

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. 

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... 

In the context of C-H activation processes, the major issue here is the regioselectivity of the functionalization as determined by the acidity of the C-H bonds or factors that influence a concerted metallation-deprotonation (CMD) pathway [la, 5]. 

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. 

The oxidative coupling of benzothiazoles with azine JV-oxides is promoted by catalytic Pd(OAc)2 and CuBr and stoichiometric Cu(OPiv)2 (eq 142). The copper pivalate salt plays a dual role oxidant and concerted metalation-deprotonation (CMD) promoter, while the role of copper bromide is less obvious. 

Coupling Reactions. Palladium pivalate is an effective catalyst for mild and efficient direct arylation reactions. One account described the intramolecular arylation phenolic ethers (eq 1). Initial optimization with Pd(OAc)2 in conjunction with electron-deficient phosphines led to the desired biphenyl in low yield. Upon the addition of carboxylic acid additives, the yield improved markedly with the optimal additive being pivalic acid. Indeed it was determined that the additive was not needed when Pd(OPiv)2 was errqtloyed as a catalyse although improved yields were observed when the title compound was used in conjunction with the acid additive. The role of the pivalate is believed to be that of a proton shuttle in a concerted metallation-deprotonation (CMD) sequence. A further advantage of using Pd(OPiv)2 was the rate enhancement of the arylation with most reactions complete in less than 6 h (vs. 12 or more hours with Pd(OAc)2). The catalyst was applied to a range of electron-rich and -deficient arenes with good to excellent yields. 

More complex mechanisms may involve the deprotonation of a substrate that is bound to the transition metal. The bidentate nature of the acetate anion is critical in some palladium-catalyzed direct arylation/C-H activation reactions. In these reactions, the acetate moiety participates in a concerted metalation-deprotonation (CMD) step wherein a transition metal-bound acetate group removes a proton from an aryl C(sp2)-H bond as the metal-C(sp2) bond is being formed (eq 32). Many acetate bases have been used (e.g., KOAc, NaOAc, CsOAc, and CsPiv), and the optimal base used in these reactions is generally determined during the optimization process. 

The C-H bond activation process by Ru(OAc)2(p-cymene) and Pd(OAc)2 can be compared by kinetic study of their reaction with phenylpyridine leading in both cases to a cyclometallate complex. Although the reaction with Pd(OAc)2 is faster than with the ruthenium(II) catalyst, it is not affected by addition of acetic acid or acetate, thus the reaction with Pd(OAc)2 proceeds - to the difference of Ru(OAc)2L - via an intramolecular non-autocatalysed Concerted Metallation-Deprotonation (CMD) mechanism [91]. 

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