Palladium-Catalyzed Reactions Involving Nucleophilic Substrates

Palladium-Catalyzed Reactions Involving Nucleophilic Substrates 

The o-complexes generated by oxidative addition of haloarenes and haloalkenes to paUadium(O) are electrophilic at the metal-substituted center and can therefore react with nucleophiles other than alkenes, especially with enolate and homoenolate ions to form new C-C bonds [331, 332]. This reaction mode has been termed anion capture [333]. 

After insertion of the palladium into the carbon-oxygen bond of the trienyl triflate 120, the (S)-BINAP (2,2 -bis(diphenylphosphinyl)-l,l -binaphthalene) ligand on the palladium led to selective coordination to one of the enantiotopic double bonds with subsequent cyclization to give the intermediate tt-allyl complex 124. This was regio- and stereoselectively trapped by the nucleophile. Further elaboration of 121 gave the natural product with good optical purity. 

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Palladium-Catalyzed Reactions Involving Nucleophilic Substrates... 

Substitution reactions of allylic substrates with nucleophiles have been shown to be catalyzed by certain palladium complexes [2, 42], The catalytic cycle of the reactions involves Jt-allylpalladium as a key intermediate (Scheme 2-22). Oxidative addition of the allylic substrate to a palladium(o) species forms a rr-allylpal-ladium(n) complex, which undergoes attack of a nucleophile on the rr-allyl moiety to give an allylic substitution product. The substitution reactions proceed in an Sn or Sn- manner depending on catalysts, nucleophiles, and substituents on the substrates. Studies on the stereochemistry of the allylic substitution have revealed that soft carbon nucleophiles represented by sodium dimethyl malonate attack the TT-allyl carbon directly from the side opposite to the palladium (Scheme 2-23). 

Jia and coworkers [71] reported a very nice palladium-catalyzed domino reaction involving a C-H activation process (Scheme 12.47). The regioselectivity of the attack of the nucleophile at the intermediately formed palladacyle 121 is solely controlled by the reaction conditions using the same substrate. In the Pd-catalyzed transformation of 120 in DMF in the absence of water, the aryl-substituted product 122 was obtained in 47-95% yield, and, in the presence of water, the alkyl-substituted product 123 in 60-95% yield. However, it should be noted that the reaction temperature has also some influence. The paUadacycle intermediate 121 was successfully trapped by cyanation, Heck reaction, secondary C-H activation, and Suzuki coupling. 

Palladium-catalyzed allylic substitution reactions, known as Tsuji-Trost reactions, are a well-established method for carbon-carbon bond forming processes [48]. The generally accepted mechanism for this reaction involves the oxidative addition of the allylic substrate to Pd(0) to provide a Jt-allylpalladium complex. The subsequent reaction of the electrophilic 7t-allylpalladium complex with the nucleophile affords the substituted product and Pd(0), which is regenerated to start the catalytic cycle (Scheme 7.26). 

The generally accepted mechanism for Pd-catalyzed allylic substitution involves association of the palladium(0) catalyst to the substrate, and oxidative addition to provide a ir-aUyl complex. The equilibrium between the neutral 7r-allyl complex and the more reactive cationic 7r-allyl complex depends on the nature/concentration of phosphine Ugand. Nucleophilic addition to the ligand involves direct attack on the ligand when stabilized enolates are employed. After dissociation of the product, the palladium is able to continue in the next catalytic cycle (Scheme 2). In general, the reaction proceeds via a Pd(0)/Pd(II) shuttle, although a Pd(II)/Pd(IV) pathway is also possible. 

While palladium-catalyzed alkenylation reactions involving amines as nucleophiles have been extensively explored, the related copper-catalyzed processes are rare and only few examples have been reported in the literature. The first example was described in 2001 and implied the particular use of l,3-dibenzyl-5-iodouracil as electrophilic counterpart for the access of enamine-type products with potential pharmacological activity (Scheme 20) [87]. The authors demonstrated that the conditions previously reported by Buchwald for the arylation of imidazoles [88] were suitable for the vinylation of numerous amines (including primary heteroaromatic substrates and both primary and secondary aliphatic ones) to yield thus the corresponding 5-aminouracil derivatives in yields up to 78%. 

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