Practical Aspects of Carbon-Carbon Cross-Coupling Reactions Using Heteroarenes

The use of cross-coupling reactions for the preparation of alkylated and arylated heteroaromatic compounds has increased tremendously over the past two decades. This has been driven on the one hand by the increasingly complex structures of new drugs, most of which contain one or more heterocyclic motifs. On the other hand, the development of new catalysts and reaction conditions for these reactions has rendered even the most unreactive of heteroarenes amenable to cross-coupling chemistry. Not only have new bulky electron-donating ligands been created that allow the coupling of aryl chlorides under mild conditions, but also the use of ligand-free palladium, in particular at very low doses, sometimes called homeopathic palladium, has Served to bring down the cost of these reactions. More recent and enabling developments are the use of catalysts based on cheap metals such as nickel, copper, and iron. Scale-up issues are availability and cost of starting materials, cost of the catalysts (related to cost of the metal and the ligand, intrinsic activity and stability of the catalyst), solvent choice, and removal of the metal to <10 ppm from the final product. This latter point is aggravated with heteroaromatics as they tend to be good ligands for the transition metal. For the same reason substrate and product inhibition are quite common.