Palladium-Catalysed Coupling Reactions

Palladium-catalysed coupling reactions have gained importance as a tool for the production of pharmaceutical intermediates and to a lesser extent also for the production of agrochemicals, flavours and fragrances, and monomers for polymers. In this review only these cases are discussed where it seems highly likely that the technology is or has been used for ton-scale production. We document twelve cases where the Mizoroki-Heck reaction was used to arylate an alkene. In two of these cases allylic alcohols were arylated, leading to the aldehyde or the ketone. The Suzuki reaction has been used mostly to produce biaryl compounds from aryl halides and arylboronic acid derivatives. Twelve processes were recorded. Ortho-tolyl-benzonitrile, a biaryl compound produced via the Suzuki reaction, is used as an intermediate in six different pharmaceuticals all belonging to the Sartan group of blood pressure-lowering agents. The Kumada-Corriu reaction in which an aryl or alkenyl Grignard is coupled to an aryl or alkenyl halide was used nine times. In these coupling reactions palladium is often replaced by the much cheaper nickel or iron catalysts. The Negishi reaction couples an arylzinc halide with an aryl or alkenyl halide. These reactions are fast and highly selective; the only drawback being the stoichiometric zinc waste. Two cases were found. In one of these it was possible to use only a catalytic amount of zinc (double metal catalysis). The Sonogashira reaction couples a terminal alkyne to an aryl or alkenyl halide. Three cases were found. Acetylene is usually not coupled as such in view of its instability. Instead, trimethylsilylacetylene or the acetylene acetone adduct is used. Finally, one case was found of a palladium-catalysed allylic substitution and one case of a CH-activation reaction to form a benzocyclobutane ring. Most of these reactions were implemented in production in the past ten years.