Reductive organometallic reagents

Nitriles are similar in some respects to carboxylic acids and are prepared either by SN2 reaction of an alkyl halide with cyanide ion or by dehydration of an amide. Nitriles undergo nucleophilic addition to the polar C=N bond in the same way that carbonyl compounds do. The most important reactions of nitriles are their hydrolysis to carboxylic acids, reduction to primary amines, and reaction with organometallic reagents to yield ketones. 

The most common reactions of carboxylic acid derivatives are substitution by water (hydrolysis) to yield an acid, by an alcohol (alcoholysis) to yield an ester, by an amine (aminolysis) to yield an amide, by hydride ion to yield an alcohol (reduction), and by an organometallic reagent to yield an alcohol (Grignard reaction). 

Among the a-hetero-substituted chiral organometallic reagents, a-lithio ethers 2 are an important class of compounds. A general route to these compounds is the reductive lithiation of a-(phcnylthio) ethers 1 with lithium (dimethylamino)naphthalenide (I.DMAN)4,5. The generality of this method lies in the ready availability of various types of a-(phenylthio) ethers. 

Reduction by hydride transfer from the organometallic reagent can become predominant if bulky organometallics are employed. 

In contrast cyclic y-(rey/-butyldimethylsilyloxy)-a,/ -unsaturated sulfones undergo addition of organometallic reagents to give mainly trans-adducts after reductive removal of the sulfonyl group. 

The general mechanism of coupling reactions of aryl-alkenyl halides with organometallic reagents and nucleophiles is shown in Fig. 9.4. It contains (a) oxidative addition of aryl-alkenyl halides to zero-valent transition metal catalysts such as Pd(0), (b) transmetallation of organometallic reagents to transition metal complexes, and (c) reductive elimination of coupled product with the regeneration of the zero-valent transition metal catalyst. 

These are called cross-coupling reactions and usually involve three basic steps oxidative addition, transmetallation, and reductive elimination. In the transmetallation step an organic group is transferred from the organometallic reagent to palladium. 

Now we see an analogy with the LAH reduction sequence (see Section 7.11), in that this ketone intermediate also reacts with the organometallic reagent, rather more readily than the initial carboxylic acid derivative, so that this ketone cannot usually be isolated. The final product is thus a tertiary alcohol, which contains two alkyl or aryl groups from the organometallic reagent. 

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