Overview of Cross-Coupling

Catalytic nucleophilic substitution reactions comprise some of the most commonly used catalytic processes in S)mthetic organic chemistry. Substitutions at aromatic and vinylic halides and sulfonates, sho vn generically in Equation 19.1, are commonplace in the preparation of pharmaceutical candidates, have often been used in the s)mtheses of natural products, and have been used many times in the syntheses of sophisticated conjugated organic materials. These metal-catalyzed reactions are typically called cross-coupling reactions.  

In addition to coupling reactions that occur with aryl and vinyl nucleophiles and electrophiles, coupling reactions that occur with sp -hybridized nucleophiles or electrophiles have been developed. These reactions include those that form tertiary and quaternary stereocenters from racemic or prochiral nucleophiles, as shown in Equation 19.4. Substitution reactions at propargylic and benzylic electropliiles have also been reported, and several groups have reported in recent years progress in metal-catalyzed substitutions of alkyl electrophiles, including enantioselective substitutions of aliphatic organic halides. 

Finally, coupling reactions that occur without a leaving group, a main group metal reagent, or both have been reported. These direct arylation reactions are a form of C-H bond activation, typically of aromatic or heteroaromatic C-H bonds. Due to the close relationship between these processes and cross-coupling reactions, however, direct arylations are described in the final section of this chapter after copper-catalyzed coupling processes. 

this chapter focuses on the most investigated classes of metal-catalyzed coupling reactions—namely, reactions of aromatic and aliphatic electrophiles with main group carbon or nitrogen nucleophiles, reactions of aromatic halides with olefins, including enanti-oselective versions of these reactions, and direct coupling processes. The mechanisms of these reactions are presented with reference to the chapters on the stoichiometric steps of these catalytic processes. 

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