Palladation, electrophilic

The role of acetic acid in such oxidative cyclization processes is to protonate the acetate ligand, making Pd(II) more electrophilic, thereby promoting the initial electrophilic palladation of the aromatic ring. 

An electrophilic palladation by a phenyl palladium intermediate at C(3) and a C(3) to C(2) migration of a palladium species, followed by reductive elimination, is indicated. 2-Phenylpyridine has been formed by the reaction of pyridine and iodobenzene at 150 °C in the presence of phosphido-bridged ruthenium dimer complexes.49 A catalytic cycle involving one of the complexes in the system was proposed. Optimum conditions for the efficient and regioselective palladium-catalysed C(2) arylation of ethyl 4-oxazolecarboxylate (47) with iodobenzene have been presented.50... 

Heteroaromatics have high reactivity toward electrophilic palladation and show good regioselectivity. Reactions with pyrrole,thiophene, furan, and indole have been reported (equation 3). The use of stoichiometric copper(II) ion gives a process catalytic in Pd. 

Electronic properties of the substrate often activated C-H bonds are targeted, for example, with electron rich heteroarenes electrophilic palladation is favored at the most nucleophilic position and relies on the inherent reactivity of the system. Similarly if a proton-transfer pathway is under operation, activation is favoured on the most acidic C-H bond. 

Utilization of activated C-H bonds in heteroaromatic compounds is particularly suited to these transformations, where the key C-H activation step involves electrophilic palladation at an electron deficient Pd(II) catalyst. Fujiwara et al. 

Electrophilic palladation directed by the electronic and steric properties of the W-protecting group... 

The electron-rich nature of heterocycles such as indoles, furans and thiophenes allows a different type of Heck reaction to be carried out. In this oxidative modification, the aryl palladium derivative is generated by electrophilic palladation with a palladium(II) reagent. 

It is not clear whether the palladium-mediated cycUsations of anilino-acrylates and related systems operate via a Heck sequence or via an electrophilic palladation of the enamine. 

Another Wacker-type oxidation is the oxidative cyclization reaction, which is the intramolecular union of two arenes with formal loss of H2 promoted by a Pd(II) species [typically Pd(OAc)2].33-36 In an early example of this transformation, treatment of diphenylamines 45 with Pd(OAc)2 in acetic acid yielded carbazoles 46.37 The role of acetic acid in such oxidative cyclization processes is to protonate one of the acetate ligands, which affords a more electrophilic cationic Pd(II) species, thereby promoting the initial electrophilic palladation of the aromatic ring. 

The electron-rich nature of heterocycles such as indoles, furans, and thiophenes allows a different type of Heck reaction to be carried out. " In this oxidative modification the aryl palladium derivative is generated by electrophilic palladation with a palladium(II) reagent. This process is not catalytic in the standard way, but can be made so by the addition of a reoxidant selective for Pd(0) note, that the catalytic Pd(0) could not effect the first (electrophilic) ring palladation. " ... 

A -Methyl-2-pyridone undergoes electrophilic palladation at C-5, allowing a subsequent direct coupling via a modified Heck reaction (cf. section 2.7.2.1). ... 

Even indoles bearing acyl or phenylsulfonyl substituents on nitrogen, are easily palladated at moderate temperatures, substitution occuring at C-3, or at the 2-position if C-3 is occupied. The metallated products are seldom isolated but allowed to react with acrylates, other alkenes (Heck reaction), or carbon monoxide in situ. Although electrophilic palladation normally requires one equivalent of palladium(II), the incorporation of reoxidants selective for Pd(0), such as t-butyl perbenzoate or copper(II) compounds, allows catalytic conversions to be carried out. ... 

Subsequent studies revealed that the pre-activation of the arene was not required when an oxidant was present (15) [134, 135]. While the mechanism has yet to be fully investigated, preliminary studies have ruled out both radical and electrophilic palladation pathways. 

Heck reaction conditions have been applied to introduction of the dehydroalanine side-chain on to indoles. Under catalytic conditions, 4-bromo-l-tosylindole is converted to the 4-isomer of dehydrotryptophan in 90% yield. However, with a stoichiometric amount of PdClj in acetic acid the 3 position was substituted, albeit in only 17% yield. A much better yield of the 3-substitution product was obtained by changing from acetyl to an N-ethoxycarbonyl protecting group in the dehydroalanine. <94CPB832> Both of these reactions presumably involve indolylpalladium species. Under the Heck conditions the 4-indolylpalladium(II) species is formed by oxidative addition. With the stoichiometric amount of PdClj, the dominant reaction is electrophilic palladation at the 3-position. 

Vinylation can be carried out directly at the 3-position on indoles without a halogen or sulfonate substituent <84H(22)1493>. This reaction presumably involves an electrophilic palladation at C3 followed by a Heck reaction (Equation (116)). These reactions can also be carried out in the presence of a cooxidant such as Cu(OAc)2 or AgOAc which serves to reoxidize palladium. Similar reactions have been carried out on 1-benzenesulfonylindole <84S236> and 1-acylindoles <83JCS(Pl)l36l>. 

The formation of several 2-aminobenzothiazoles via palladium-catalyzed, direct intramolecular oxidative C-H functionalization was recently demonstrated by Batey at the University of Toronto. The substrates used were A -aryl thioureas which in the presence of an interesting co-catalytic Pd(PPh3)4/Mn02 system under oxygen atmosphere, yielded the desired products. In terms of the mechanism, this transformation proceeded presumably through electrophilic palladation, suggested by the higher reactivity of the more electron-deficient substrates. 

Oxidative cyclizations are generally facilitated by the use of Pd(OAc)2 in acetic acid under reflux. The initial step in these oxidative cyclization reactions is believed to be the electrophilic palladation of the aromatic ring. An example is presented in the preparation of anti-malarial agent quindoline, isolated from a West African plant Cryptolepis sanguinolenta, which was synthesized through an oxidative cyclization of the appropriately 3-substituted quinoline in the presence of two equivalents of Pd(OAc)2 in trifluoroacetic acid. ... 

Reaction of the imine 50, derived from o-iodoaniline and benzaldehyde, with diphenylacetylene afforded a mixture of the quinoline 53 and the isoindolo[2.1-ajindole 56. Formation of the quinoline can be understood by insertion of the C=N bond in 51, which is regarded as 6-endo cyclization of the intermediate 51 to generate 52, followed by -H elimination to yield the quinoline 53. On the other hand, the isoindolo[2.1-a]indole 56 is formed by 5-exo cyclization of 51 to produce 54. The final step is the electrophilic palladation of the a-palladium intermediate 54 to the adjacent aromatic ring to give 55, and reductive elimination gives rise to 56 [18]. The isoindolo[2.1-a]indole 59 was obtained in high yield from alkylarylacetylene 58 and the imine 50 [19]. 

It was demonstrated by Heck in the late 1960s that arylpaUadium salts, prepared by trans-metallation of organomercury compounds, constitute useful reactants in various vinylic substitution reactions.f t Independently, Moritani, Fujiwara, and colleagues conducted similar vinylic substitutions, but generated the organopalladium intermediates by direct electrophilic palladation of arenes.t ° In these reactions the palladium(II) salt employed is reduced to paUadium(O) (Scheme ). ... 

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