Exploring pre-catalyst scope and selectivity in Negishi coupling of aryl iodides in deep eutectic solvents

Abstract

Negishi coupling is a valuable synthetic protocol for the formation of C–C bonds. However, the use of highly reactive alkyl- or arylzinc reagents in these reactions usually requires them to be performed under strictly anhydrous conditions using Schlenk techniques. It has recently been demonstrated that using deep eutectic solvents (DES) as reaction media allows Negishi reactions to be performed without any protection from air or moisture. This paper explores pre-catalyst scope and regioselectivity in these reactions. This has led to new protocols using cheap and readily available Pd pre-catalysts, e.g. Pd₃(OAc)₆, whilst allowing coupling of some ortho-functionalised aryl iodides without the need for a supporting phosphine ligand. Unusual solvent-induced selectivity is demonstrated, which allows highly regioselective C–C bond formation to take place, even when multiple C–I bonds are present on the aryl iodide precursor. To further understand this, the activity and selectivity of a range of Pd pre-catalysts towards different iodoarenes has been explored, with the results helping inform the choice of catalyst for specific substrates and desired regioselectivity. The use of DES in these reactions promises to simplify their use, especially in environments where strict exclusion of air and moisture is not possible, whilst simultaneously providing access to regioselectivity that does not occur in conventional solvents under the same conditions.