Reactions with Stabilized, Soft Nucleophiles

By far, the most often used nucleophiles are malonates, which can be deproto-nated by the aUcoxide formed in the reaction of allyl carbonates or by an added base such as NaH. This standard nucleophile has been applied in all types of aUylations, and many applications are also reported in this monograph. The nucleophihc species can also be generated by 1,4-addition, for example, of alkoxides, generated from carbonates, onto alkylidenemalonates both inter- and intramolecularly [92]. The substitution products can be subjected to a thermal desalkoxycarboxylation or, after hydrolysis, decarboxylation, giving rise to carboxylic esters or acids [93]. Therefore, in combination with this decomposition, malonates can also be used as surrogates for ester enolates [94], which generally cannot be used as nucleophiles in allylations. 

Reactions with fS-keto esters in general are not as easy as those with malonates for several reasons in contrast to the symmetrical malonates, reactions of fS-keto esters, as well as all other unsymmetrical nucleophiles, generate a stereogenic center that is configurationally labile (if a-CH is present), giving a mixture of stereoisomers. 

In addition, one has to consider the possibility of C- versus O-allylation, and for intramolecular processes, products with different ring sizes may be obtained [96]. 

If nucleophiles activated by one or two sulfonyl groups are used, the sulfonyl residues can be removed afterward under reductive conditions [97] or by elimination [98]. Nitro compounds can easily be reduced to the corresponding amines [90], 

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Soft nucleophiles react with overall retention of stereochemistry with suitable substrates (Scheme 14). For example, the relative stereochemistry of cyclohexenyl acetate 90 is retained upon reaction with stabilized enolates. ... 

The soft-nucleophile-soft-electrophile combination is also associated with a late transition state, in which the strength of the newly forming bond contributes significantly to the stability of the transition state. The hard-nucleophile-hffld-elechophile combination inqilies an early transition state with electrostatic attraction being more important than bond formation. The reaction pathway is chosen early on the reaction coordinate and primarily on the basis of charge distributiotL... 

Soft nucleophiles (Nu) generally give the best results so, for carbon-carbon bond formation, stabilized enolates such as malonates are best, but for C-X (X = O, N, S) bond formation the reaction is successful with alkoxides, amines, cyanide, and thioalkoxides. This example shows an amine attacking outside the ring probably because the alkene prefers to be inside the ring. 

The most important class of allylic substitutions are palladium-catalyzed reactions with so-called soft nucleophiles such as stabilized carbanions or amines, and with few exceptions, the enantioselective transformations discussed in this chapter belong to this category. The mechanism of these reactions has been firmly established and a detailed picture of the catalytic cycle can be drawn [1, 2,3,4,5,6,13,14,15]. The course of allylic substitutions catalyzed by metals other than palladium is less clear and information about the intermediates involved is scarce. 

Whereas the vast majority of C —C bond forming nucleophilic additions to 7t-allylpalladium complexes are performed with soft carbanions stabilized by two electron-withdrawing groups (see Section 1.5.6.1.), certain enol derivatives of monocarbonyl compounds and aza-analogs can also be used. In view of the extraordinary importance of these nucleophiles for organic synthesis, their reactions with either stoichiometrically or catalytically generated 7r-allylpalladi-mn complexes are treated separately in this section. 

These results may be understood in the context of soft-hard acid-base theory.As mentioned earlier, the Fischer carbene complexes can be regarded as soft electrophiles, especially the alkylthio complexes. Hence, the adducts 99 formed by the reaction of 98b with a thiolate ion nucleophile enjoy enhanced stability due to the symbiotic effect of adding a soft nucleophile. This stabilization apparently reduces the need for additional stabilization by the phenyl substituent, which translates to a reduced p(Ki) value. 

Intennolecular termination processes by carbon nucleophiles will be considered separately for reactions with soft nucleophiles (i.e., mostly stabilized enolates) and with organometal-lic compounds such as stannanes, boranes, and zincates. 

Exceptions can only be observed if steric interactions either between the substituents in the allyl substrate [14] or between the allyl moiety and the ligands [15] destabilize the syn,syn-complex. However, selective palladiumotalyzed conversions of (Z)-allyl substrates with retention of the alkene geometry is not a trivial issue. A transfer of the (Z)-configuration from the allyl substrate to the product would only be possible, if the reaction could be carried out at low temperatures (below —60 °C) at which isomerization reactions do not yet take place. This can only be achieved with highly reactive nucleophiles such as chelated ester enolates, but not with the generally used stabilized soft C-nucleophiles [16]. 

When a stabilized enolate undergoes a 1,4-conjugate addition with an enone, it is called a Michael reaction. However, many related reactions with analogous mechanisms are also described as Michael additions. Any C=C double bond containing one or more EWGs is referred to as a Michael acceptor and soft nucleophiles that prefer 1,4-addition, including stabilized enolates and organocuprates, are described as Michael donors. ... 

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