The technique of high-speed ball milling (HSBM) has recently been shown to provide a useful solvent-free route to the reduction of esters using a mild reducing agent. HSBM is a technique that utilizes a ball-bearing agitated at high speed to provide the energy for the reaction. Due to the noted differences in reactivity between HSBM and solution based chemistry, an investigation of coupling reactions was undertaken to produce a greener syntheses of these types of reactions.

Transition-metal-catalyst cross-coupling reactions are very important in the field of organic synthesis. Among these, the coupling between aryl halides and terminal alkynes to produce aryl alkynes, known as the Sonogashira reaction, is important for the manufacture of natural products, pharmaceuticals, and other organic materials. Traditionally, this reaction is carried out using a phosphane-palladium complex catalyst, catalytic copper halide, and triethyl amine. Among the several drawbacks in the use of Sonogashira couplings are high loadings of palladium catalyst and the use of copper salts. The presence of copper salt can promote homo-coupling of the reactants, thus resulting in costly separation procedures and loss of valuable starting materials. A method that could result in the elimination of copper salts and solvents, while utilizing a low catalyst load would be desirable.

To date a method has been developed for a solvent-free Sonogashira coupling using HSBM conditions. Using this method it has been found that the use of copper salts is unnecessary. Also, it has been found that small catalytic loading is possible. Initial results indict that the use of Pd(0) in place of a Pd(II) catalyst is possible. This represents a solvent and copper free methodology that results in the generation of less chemical waste, in a more atom economical manner.