Carbanion reagents, nonstabilized

Nucleophilic substitution in electrophilic azine positions with nonstabilized carbanionic reagents is difficult to effect. It has been found, however, that sulfoxides derived from an electrophilic azine position can react with a Grignard reagent with replacement of the sulfinyl group and carbosubstitution <90AHC(48)l>. 

The above system failed entirely when nonstabilized carbanions such as ketone or ester enolates or Grignard reagents were used as carbon nucleophiles, leading to reductive coupling of the anions rather than alkylation of the alkene. However, the fortuitous observation that the addition of HMPA to the reaction mixture prior to addition of the carbanion prevented this side reaction1 extended the range of useful carbanions substantially to include ketone and ester enolates, oxazoline anions, protected cyanohydrin anions, nitrile-stabilized anions3 and even phenyllithium (Scheme 3).s... 

Since the anion N is a nonstabilized carbanion, an organometallic nucleophile such as an organolitliium or a Grignard reagent could be prepared from the corresponding bromide. 

While most of the chemistry discussed in this chapter has been developed in the past decade, several important methods have withstood the test of time and have made important contributions in areas such as natural product synthesis. Methods such as cuprate acylation and the addition of organolithiums to carboxylic acids have continued to enjoy widespread use in organic synthesis, whereas older methods including the reaction of organocadmium reagents with acid halides, once virtually the only method available for acylation, has not seen extensive utilization recently. In the following discussion, we shall be interested in cases where selective monoacylation of nonstabilized carbanion equivalents has been achieved. Especially of concern here are carbanion equivalents or more properly organometallics which possess no source of resonance stabilization other than the covalent carbon-metal bond. Other sources of carbanions that are intrinsically stabilized, such as enolates, will be covered in Chapter 3.6, Volume 2. 

In this chapter, the substitution reactions of organometallic reagents with organic halides and related electrophiles are reviewed. - The major portion of the chapter is devoted to a discussion of organocopper compounds, which first transformed the alkylation of nonstabilized carbanions into a reaction of general synthetic utility. More recently, transition metals other than copper have also found widespread application in such coupling reactions, and developments in this area are outlined in Section 1.5.3. 

The importance of a branched chiral amines in nature and as substructures in biologically active unnatural products led to the rapid development of an impressive number of methods to synthesize this class of compounds in enantiomerically enriched forms. It is quite spectacular to see how many very efficient methods have appeared since the early twenty first century. Furthermore, catalytic asymmetric methods now exist to transfer sp , sp, or sp nonstabilized carbanion nucleophiles to a wide range of activated imines. Even if the past 10 years have witnessed phenomenal advances in this area, Ellman s chiral auxiliary method is still very attractive. Indeed, it is the only one that allows the addition of the three kinds of nucleophiles using the same dass of reagents and it also possesses numerous other... 

Reaction of nonstabilized carbanions with [Fp(olefin)] complexes generally results in either displacement of the olefin or reduction of the metal rather than formation of stable (j -alkyliron complexes. This is especially true with simple, nonstabilized organo-magnesium halide or lithio reagents. However, allylmagnesium chloride and phenylmag-nesium chloride react in modest (20-40%) yield with the ethylene, propene and butadiene (1,4 addition) iron complexes. Lithium dimethylcuprate is even more efficient, reacting in up to 70% yield with Fp complexes of styrene, butadiene (1,4 addition) isoprene (1,4 addition) and allene. Complexes of cyclopentene and allene react in low... 

Many studies of the addition of nucleophiles to palladium-allyl complexes have been conducted. Hayashi has shown that the additions of stabilized anions, such as malonate anions or amine nucleophiles, to chiral, non-racemic allyl complexes occur with inversion of configuration.Addition of excess phosphine and either diethyl malonate or dimethylamine to a chiral, non-racemic allyl complex results in nucleophilic attack with nearly complete inversion. The reaction with sodium dimethylmalonate is shown at the right of Equation 11.40. In contrast, nonstabilized carbanions such as allyl or phenyl magnesium chloride react with the same Ti -allylpalladium complex with retention of configuration as shown at the left of Equation 11.40. The stereochemistry from reaction of the Grignard reagents likely results from nucleophilic attack at the metal, followed by reductive elimination. 

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