Crosscouplings

Crosscouplings are reactions in organic synthesis in which two fragments are joined by forming a new covalent bond, most often a carbon–carbon bond, through the use of a transition-metal catalyst. The most widely used metal is palladium, though nickel and other metals are also employed. A typical catalytic cycle involves oxidative addition of the metal into an electrophilic partner (such as an aryl or vinyl halide or triflate), transmetalation with an organometallic nucleophile, and reductive elimination to forge the new bond and regenerate the active catalyst.

Several families of cross-coupling reactions have become standard tools. In Suzuki–Miyaura coupling, an organoboron reagent couples with an organohalide or pseudohalide; Negishi coupling uses organozinc reagents; Stille uses organostannanes; Kumada uses Grignard reagents; Sonogashira couples alkynes with aryl or vinyl halides; and the Heck reaction couples aryl or vinyl halides with alkenes. In addition, C–N and C–O cross-couplings (Buchwald–Hartwig amination, Chan–Lam-type couplings) are widely used to form heteroatom bonds via cross-coupling platforms.

Crosscouplings enable rapid assembly of biaryl motifs, vinyl and alkyl–aryl linkages, and complex architectures used in pharmaceuticals, natural products, and materials science. Practical considerations include the choice of catalyst and ligand, base, solvent, and the leaving group on the electrophile, as well as the preparation of the organometallic partner. While powerful, many cross-couplings rely on expensive metals and can generate metal residues; some families involve toxic tin reagents, and nickel-based methods are often employed to broaden substrate scope and reduce cost.

Recent developments include nickel- and palladium-catalyzed cross-couplings with challenging substrates, cross-electrophile couplings, and photocatalytic or dual photoredox–metal catalytic variants that proceed under milder conditions and with different reactivities.