Halogen-metal exchange stereochemistry

Metal-14 anions react with alkyl halides (RX) mostly by nucleophilic substitution (Sn2), the stereochemistry of which is dependent on the structure of R and X, the solvent and the nature of the counterion. Other reactions were also observed nucleophilic substitution at halogen [also called halogen/metal exchange (HME)] and single electron processes. In some cases steric hindrance around the reactant results in elimination. 

It is essential, for successful retention of stereochemistry, to form the organolithiums by halogen-metal exchange, and not by reductive lithiation. While transmetallation of cis- and trans-24 with BuLi, quenching the organolithium 25 with ethylene oxide, gives complete retention of stereochemistry in 26. Owing to the intervention of radicals, reductive lithiation leads to considerable (but not total) epimerisation ... 

Bis(pinacolato)diboron 8 also reacts with 1-halo-l-lithioalkenes 10 (available from 1,1-dihaloalkenes or 1-haloalkenes by halogen-metal exchange or metalation reaction, respectively) to afford 1,1-bismetalated dienes 11. These are readily converted into polysubstituted dienes through various transition metal-catalyzed carbon-carbon bond formations (Scheme 4) [29]. However, these seemingly attractive methods must not hide the problems of the stereochemistry and regiospecificity of the subsequent cross-coupling reactions. 

The transient anomeric lithiation shown in Scheme 3.2.1 differs from standard halogen-metal exchanges in that a reductive mechanism is involved. The use of reductive methods, illustrated in Figure 3.2.2, is complimentary to the exploitation of metal exchange reactions for the formation of glycosidic nucleophiles in that strategies towards selectivity in the anomeric stereochemistry become available. 

One of the most direct routes to vinylsilanes uses vinyl halides as starting materials. Metal-halogen exchange, followed by electrophilic attack by TMSC1, can often provide the vinylsilane quickly and in good yield. As an added bonus, vinyl bromides have been shown (10, II) to proceed through this sequence with retention of double-bond stereochemistry. 

The synthetic protocol for many of these reagents is detailed elsewhere9. Note that stereochemistry in EIZ alkenes is preserved in the formation of both the fluorinated vinyl-lithium and the fluorinated vinylzinc reagents, and that hindered bases permit selective metallation vs. metal/halogen exchange. 

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