Palladium reaction with nucleophiles

Although brominated derivatives of the five-membered heterocycles may be prepared by reactions of the co-ordinated ligands, these may then undergo further reactions with nucleophiles. As an example, the nucleophilic displacement of bromide from 8.15 by sulfide has been used to form new macrocyclic systems (Fig. 8-12). The palladium probably serves a dual function in this reaction. First, it organises the open-chain ligand such that the two reactive sites are held in proximity, so allowing the intramolecular formation of the sulfide and, second, it may activate the pyrrolic ring to nucleophilic displacement of bromide. 

Palladium-catalyzed reactions with nucleophilic substrates... 

Wacker-type oxidative reactions of olefins with nucleophiles, reactions of zr-allyl-palladium complexes with nucleophiles, reactions based on chelation, and trans-metallation of organomercury compounds. 

D.1. Reactions with Nucleophiles. Previously, a jr-allylic palladium complex was generated by reaction of palladium reagents with allylic hydrocarbons prior to reaction with nucleophiles. In the catalytic version of this reaction, an allylic halide or an allylic acetate is used with a palladium(O) reagent. Why use a palladium complex when enolate alkylation is a well-known process (sec. 9.3.A) A typical enolate coupling reaction is the conversion of 2-methylcyclopentane-l,3-dione (373) to the enolate anion by reaction with NaOH, allowing reaction with allyl bromide. Under these conditions only 34% of 374 was obtained. When allyl acetate was used in place of allyl bromide in this reaction and tetra w(triphenylphosphino)palladium was used as a catalyst, a 94% yield of 374 was obtained.224 in this reaction, formation of the Jt-allyl palladium complex facilitated coupling with the nucleophilic enolate derived from 373, which exhibited poor reactivity in the normal enolate alkylation sequence. 

These reactions thus appear analogous to those of the substituted cyclobutadiene-nickel and -palladium halides with nucleophiles (Section VI,... 

In addition to the success just described with the well-known named processes, a number of other macrocyclization reactions mediated by palladium complexes have been reported. The first of these approaches exploits the established chemistry of palladium Jt-allyl complexes for use in activation towards reaction with nucleophiles. This reaction was employed by Harran et al. as a critical step in the construction of a series of macrocycles such as 116 via 115) designed to significantly reduce the peptidic character of known active peptides (Scheme 11.14). " The approach tolerates a variety of functionality, including alcohols, amides, thioethers and selected heteroaromatics, and was also successfully conducted on solid support. 

Based on the above-mentioned stereochemistry of the allylation reactions, nucleophiles have been classified into Nu (overall retention group) and Nu (overall inversion group) by the following experiments with the cyclic exo- and ent/n-acetales 12 and 13[25], No Pd-catalyzed reaction takes place with the exo-allylic acetate 12, because attack of Pd(0) from the rear side to form Tr-allyl-palladium is sterically difficult. On the other hand, smooth 7r-allylpalladium complex formation should take place with the endo-sWyWc acetate 13. The Nu -type nucleophiles must attack the 7r-allylic ligand from the endo side 14, namely tram to the exo-oriented Pd, but this is difficult. On the other hand, the attack of the Nu -type nucleophiles is directed to the Pd. and subsequent reductive elimination affords the exo products 15. Thus the allylation reaction of 13 takes place with the Nu nucleophiles (PhZnCl, formate, indenide anion) and no reaction with Nu nucleophiles (malonate. secondary amines, LiP(S)Ph2, cyclopentadienide anion). 

A better method for preparing primary amines is to use the azide synthesis, in which azjde ion, N3, is used for SN2 reaction with a primary or secondary alkyl halide to give an alkyl azide, RN3. Because alkyl azides are not nucleophilic, overalkylation can t occur. Subsequent reduction of the alkyl azide, either by catalytic hydrogenation over a palladium catalyst or by reaction with LiAlK4. then leads to the desired primary amine. Although the method works well, low-molecular-weight alkyl azides are explosive and must be handled carefully. 

The synthetic utility of the mercuration reaction derives from subsequent transformations of the arylmercury compounds. As indicated in Section 7.3.3, these compounds are only weakly nucleophilic, but the carbon-mercury bond is reactive to various electrophiles. They are particularly useful for synthesis of nitroso compounds. The nitroso group can be introduced by reaction with nitrosyl chloride73 or nitrosonium tetrafluoroborate74 as the electrophile. Arylmercury compounds are also useful in certain palladium-catalyzed reactions, as discussed in Section 8.2. 

C. Palladium-catalyzed reactions with oxygen nucleophiles. 

Balme and coworkers reported on a procedure for the preparation of highly functionalized furans of type 2-940 (Scheme 2.210) [480]. Their approach is based on a nucleophilic Michael addition of propargyl alcohols 2-937 to alkylidene or aryl-idenemalonates 2-938, followed by a palladium-catalyzed cydization via the carban-ion 2-939. The reactions with propargyl alcohol led to the formation of only one di-... 

Monoanions derived from nitroalkanes are more prone to alkylate on oxygen rather than on carbon in reactions with alkyl halides, as discussed in Section 5.1. Methods to circumvent O-alkylation of nitro compounds are presented in Sections 5.1 and 5.4, in which alkylation of the a.a-dianions of primary nitro compounds and radial reactions are described. Palladium-catalyzed alkylation of nitro compounds offers another useful method for C-alkylation of nitro compounds. Tsuj i and Trost have developed the carbon-carbon bond forming reactions using 7t-allyl Pd complexes. Various nucleophiles such as the anions derived from diethyl malonate or ethyl acetoacetate are employed for this transformation, as shown in Scheme 5.7. This process is now one of the most important tools for synthesis of complex compounds.6811-1 Nitro compounds can participate in palladium-catalyzed alkylation, both as alkylating agents (see Section 7.1.2) and nucleophiles. This section summarizes the C-alkylation of nitro compounds using transition metals. 

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