Organic synthesis with carbon nucleophiles

Allylpalladium complexes find wide application in organic synthesis. With carbon nucleophiles they form new C—C bonds, thus providing a method for building carbon skeletons. Dimeric allylpalladium chlorides are not very susceptible to attack by nucleophiles, but their reactivity can be enhanced by addition of triphenylphosphine, which converts them into monomeric species. These reactions, however, are stoichiometric in palladium, which is undesirable on account of its high cost. Fortunately related catalytic procedures have been discovered. Many allylic compounds react with Pd(PPhj4 (p. 181) to form cationic -allyl complexes. These cations react with nucleophiles to form substituted allylic derivatives, while the catalyst, effectively PdL , is regenerated and reenters the cycle. 

Nitroalkenes with potential leaving groups in (3-position such as a dialkylamino, an alkylthio, or a phenylsulfonyl group undergo addition-elimination reactions with nucleophiles. The chemistry of nitroenamines has been extensively investigated, and their potential utility in organic synthesis has been well established.2613 116 Severin and coworkers have developed the addition of elimination reactions of nitroenamines with carbon nucleophiles in 1960-1970, as exemplified in Eq. 4.94.117... 

Two systems have been developed to the level of useful organic synthesis methodology spontaneous coordination of the alkene to Pd and the preparation of discrete Cp(CO)2Fe-alkene cationic complexes. With the Pd system, efficient catalytic processes have been developed for the addition of heteroatom nucleophiles, while the coupling with carbon nucleophiles is mainly relegated to stoichiometric reactions these two topics will be presented separately. In the iron series, the reactions involve stable intermediates and are invariably not amenable to catalysis. 

For reviews of the reactions of CS2 with carbon nucleophiles, see Dunn, A.D. Rudorf, W. Carbon Disulphide in Organic Chemistry, ElUs Horwood, Chichester, 1989, pp. 120-225 Yokoyama, M. Imamoto, T. Synthesis 1984, 797, pp. 797-804. 

Transition metal-catalyzed allylic substitution reactions with carbon nucleophiles are among the most important carbon-carbon bond formation methods in modem organic synthesis, because of their broad substrate scope under mild reaction conditions. In addition, they are applicable to enantioselective reactions, as well as exhibiting versatility towards the alkene functionality adjacent to the chiral centre for stereoselective derivatization. Tsuji-Trost allylic substitution, involving a (Ti-allyl) metal intermediate, has provided a particular advance in this regard [34, 35]. Most recently, Sawamura et al. [36, 37] have improved the regioselectivity of this reaction with unsymmetrically substituted allylic esters, and thus opened a new approach to sertraline. 

Application of 7r-allylpalladium chemistry to organic synthesis has made remarkable progress[l]. As deseribed in Chapter 3, Seetion 3, Tt-allylpalladium complexes react with soft carbon nucleophiles such as maionates, /3-keto esters, and enamines in DMSO to form earbon-carbon bonds[2, 3], The characteristie feature of this reaction is that whereas organometallic reagents are eonsidered to be nucleophilic and react with electrophiles, typieally earbonyl eompounds, Tt-allylpalladium complexes are electrophilie and reaet with nucleophiles such as active methylene compounds, and Pd(0) is formed after the reaction. 

Organopalladium intermediates are also involved in the synthesis of ketones and other carbonyl compounds. These reactions involve acylpalladium intermediates, which can be made from acyl halides or by reaction of an organopalladium species with carbon monoxide. A second organic group, usually arising from any organometallic reagent, can then form a ketone. Alternatively, the acylpalladium intermediate may react with nucleophilic solvents such as alcohols to form esters. 

Structure B is of most interest. It is responsible for the activity of nitronates as 1,3-dipoles in [3+ 2]-cycloaddition reactions. This is the most important aspect of the reactivity of nitronates determining the significance of these compounds in organic synthesis (see e.g., Ref. 267). In addition, this structure suggests that nitronates can show both, O -nucleophilic properties, that is, react at the oxygen atom with electrophiles, and a-C-electrophilic properties, that is, add nucleophiles at the a-carbon atom. 

Besides the allylation reactions, imines can also undergo enol silyl ether addition as with carbonyl compounds. Carbon-carbon bond formation involving the addition of resonance-stabilized nucleophiles such as enols and enolates or enol ethers to iminium salt or imine can be referred to as a Mannich reaction, and this is one of the most important classes of reactions in organic synthesis.104... 

Recently, acylsilanes have been utilized as useful intermediates in organic synthesis [57], For example, treatment of acylsilanes with the fluoride ion generates the corresponding acyl anions which react with electrophiles. On the other hand, by using the electrochemical method, acylsilanes serve as acyl cation equivalents because nucleophiles are introduced at the carbonyl carbon. Chemical oxidation of acylsilanes with hydrogen peroxide which affords the corresponding carboxylic acids has been reported [58], However, the anodic oxidation provides a versatile method for the introduction of various nucleophiles... 

Alkoxycarbenium ions are important reactive intermediates in modem organic synthesis.28 It should be noted that other names such as oxonium ions, oxocarbenium ions, and carboxonium ions have also been used for carbocations stabilized by an adjacent oxygen atom and that we often draw structures having a carbon-oxygen double bond for this type of cations.2 Alkoxycarbenium ions are often generated from the corresponding acetals by treatment with Lewis acids in the presence of carbon nucleophiles. This type of reaction serves as efficient methods for carbon-carbon bond formation. 

The point of interest is the "amphoteric" character of the allyl anion in this complex. On the one hand it may react as an anion, but on the other hand it is susceptible to nucleophilic attack by, for example, carbon centred anions. This has found widespread use in organic synthesis. The reaction with the anion releases a palladium zero complex and in this manner palladium can be employed as a catalyst. 

Epoxides are extremely useful intermediates in organic synthesis since they react with a variety of nucleophiles suffering opening of the epoxide ring with retention or inversion of configuration at the carbon undergoing attack. Thus, the development of highly stereoselective methods for the synthesis of certain chiral epoxides, such as the methods under discussion, has enabled the asymmetric synthesis of a wide variety of 1,2-bifunctional compounds. 

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