Enantioselective cross-coupling of monosubstituted ferrocenes in chiral ionic liquids

Abstract

Planarly chiral ferrocenes have applications in pharmaceuticals, agrochemicals, and biomedical research for their use as ligands or catalysts in asymmetric synthesis. Previous methods of enantioselective synthesis of planar-chiral ferrocenes involve directed ortho-metalation with either a pre-installed centrally chiral group or chiral resolution. These methods use sensitive organometallic reagents, have low atom economy, and require additional steps to remove the chiral auxiliary or perform chiral resolution. Asymmetric cross-coupling is an enticing alternative, although enantioselective C-H bond activation poses a challenge. N-heterocyclic carbenes including imidazoliums can complex to palladium catalysts to act as a chiral ligand and strong σ donor and have previously been used to achieve C-H activation in arylations of benzaldehydes. This research aimed to achieve enantioselective arylation of ferrocenes, using a catalytic system comprising Pd(OAc)2, imidazolium salts and Cs2CO3 to achieve enantioselective catalysis, enabling asymmetric cross-coupling of aryl halides to monosubstituted ferrocenes, which yielded trace amounts of product. The addition of p-benzoquinone and Cu(OAc)2- acting as oxidants- expands the scope of the reaction to facilitate asymmetric cross-coupling of monosubstituted ferrocenes with aryl boronic acids. Additionally, a homocoupling reaction between aryl bromides with 65% yield was developed, which could also offer access to axially chiral biphenyl compounds. The enantiomerically pure compounds created using these techniques have applications in many areas of organic, bio and medicinal chemistry, including drug design, ligand synthesis for asymmetric catalysis and polymer chemistry used in research, medicine, and industry.