Pathways metallation-deprotonation

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... 

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). 

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]. 

The ruthenium-catalysed arylation, by aryl halides, of benzylic amines carrying a pyridine coordinating group is thought to involve a concerted metallation-deprotonation pathway to give intermediates such as (96), followed by oxidative addition of the aryl halide to ruthenium and then reductive elimination. The reaction can be successM with aryl chlorides, as well as bromides and iodides, but here there are mechanistic differences. The ability of ruthenium to activate remote ring positions to electrophilic substitution has been referred to earlier, see Ref. 97. The reaction of ruthenium-coordinated 2-pyridyl arenes (51) with secondary alkyl halides has been shown to result in the formation of metfl-alkylated products. ... 

Lapointe D, Fagnou K (2010) Overview of the mechanistic workonthectmcerted metallation-deprotonation pathway. Chem Lett 39 1118-1126... 

A broadly applicable system for the arylation of various heterocycles with aryl bromides involves the employment of pivalic acid, along with Pd(OAc)2 and PCys (eq 160). It is h)q)othesized that the reaction involves a concerted metalation-deprotonation pathway. Other five-membered heterocycles react at the highlighted C-H position (eq 160). The same group also introduced electron-deficient fluoroarylphosphines for the direct functionalization of heteroarenes with aryl iodides. In the former report, low yields were obtained with 2-bromDpyridine or aryl halides bearing substituents such as nitro or cyano. A microwave-assisted protocol was instead developed that could overcome these limitations. ... 

Metal-catalysed biaryl formation continues to be of interest, and there has been a theoretical study of reactivity and regioselectivity in biaryl formation involving the cleavage of carbon-hydrogen bonds by a concerted metalation-deprotonation pathway. Various combinations of metal/ligand/base have been evaluated for the arylation of benzene with aryl bromides at high temperatures and pressures. The combination of cobalt(III) acetylacetonate and lithium bis(trimethylsilyl)amide proved to be effective. ... 

The palladium-catalysed reaction of the pyrazolo-pyrimidine derivative (141) with 3-bromotoluene may result in arylation at the 3-position in the pyrazole ring or at an sp hybridized site in the 7-methyl side-chain depending on the base and ligands used. After initial insertion of the palladium catalyst into the aryl halide bond, palladation of (141) occurs by a concerted metalation-deprotonation pathway and is followed by reductive elimination. Concerted metalation-deprotonation is also likely in the palladium-acetate-catalysed reaction of imidazo[l,2-a]pyridines with aryl bromides to give 3-substituted derivatives such as (142). A careful mechanistic study of the arylation of pyridine A-oxide by bromotoluene, catalysed by palladium acetate and t-butylphosphine, has shown that direct reactions of an aryl palladium complex with... 

---