Deprotonative metalation

Quite interestingly, propargyl alcohol itself can be applied in the copper-catalyzed protocol. In the absence of copper catalyst, only the metalation (deprotonation) of terminal hydrogen occurs (Scheme 38) °. 

The preferred site of deprotonation of di- or polysubstituted arenes is not easy to predict. In 1,3-disubstituted benzenes in which both substituents facilitate ortho-metalation, deprotonation will usually occur between these two groups [181, 365, 408, 416-419] (Scheme 5.45). Dialkylamino groups, however, can sometimes deactivate ortho positions (fourth reaction, Scheme 5.45), but this does not always happen [181, 420], 3-Chloroanisole [411] and 3-fluoroanisole [421] are deprotonated by organolithium compounds between the two functional groups, but the lithiated arenes dimerize readily at -78 °C, presumably via intermediate aryne formation (last example, Scheme 5.45). 

In a first approximation supra-Cp metal complexes can be prepared the same way as normal or other Cp-metal and organo-metal bonds in general. The methods used most often (see Appendix) are the metathesis reaction [Eq. (1)] followed in number by oxidative additions (Eq. (2)] and metallation/deprotonation reactions [Eq. (3)]. The latter is especially important for the cyclpentadienyl alkali metal compounds. A useful variation of reaction (3) is the formation of CpTl in an acid/base reaction from cyclopentadiene and thallium ethoxide [Eq. (3b)]. This represents a convenient route to cyclopentadienylthallium compounds, which are also valued (in place of Cp alkalis) as mild Cp-transfer reagents for the synthesis of difficultly isolable cyclopentadienyl derivatives (77). 

K CpK CpIUthf), Deprotonation with K-metal Deprotonation with K-metal >H, nC X-Ray 98 179... 

Metalation (Deprotonation from Strong Carbon Acids)... 

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...

Scheme 19 A potential conceited metallation-deprotonation reaction pathway for IV-oxide direct arylation...

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... 

Gorelsky, S.I., Lapointe, D., Fagnou, K., 2012. Analysis of the palladium-catalyzed (aromatic) C—H bond metalation-deprotonation mechanism spanning the entire spectrum of arenes. I. Org. Chem. 77, 658-668. 

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,... 

Reactions with aikynes may aiso result in the formation of cyclized products. Thus a ruthenium-catalysed reaction with aromatic amides has been used to give isoquinoline derivatives. On the basis of values of the kinetic isotope effect, A h/ d> proposed that the rate-determining step is a concerted acetate-assisted metalation-deprotonation process to yield the intermediate (30), followed by aikyne insertion and ring closure. The reaction of arylketones with alkynes may yield indenols when catalysed by rhodium cyclopentadienyl in the presence of silver and copper salts. The reaction proceeds regioselectively, so that reaction of acetophenone with 1-phenyl-1-propene... 

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). 

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