The Mechanism of the Conversion of Amines to Imines via Copper Catalysis

Abstract

Imine chemistry has deeply embedded historical roots not only in chemistry but in our wider world. The world’s first artificial penicillin was discovered from an imine and ketone, which would go on to pave the way for newer and better drugs. Imines exhibit antibacterial, antimalarial, and antifungal properties. The synthesis of imines has been explored with a variety of methods, including, but not exclusive to, amines with carbonyl compounds, amines by oxidative dehydrogenation, and amines with alkynes by hydroamination. The aim of this project was to investigate and improve the selectivity of a copper-mediated oxidative cross-coupling reaction where the synthesis of imines was favored over a secondary product, phosphoramidates. Additionally, we tried to understand how a mechanism for such selectivity might result. Alterations in the reaction conditions were explored in order to not only attempt to unravel the mechanism but also to determine what conditions favoured the desired imine product. Multiple analytical techniques such as NMR spectroscopy, infrared spectroscopy, and electron paramagnetic resonance were utilized to this effect. The formation of imine was investigated by initially altering the reaction solvents, comparing ethyl acetate, an organic solvent, to [C₄C₁im][NTf₂], an ionic liquid solvent. The rate of addition of the phosphite additive was explored, followed by the effect of the presence of different anions on the copper catalyst. Control reactions were run to isolate the effect of each starting material, as well as reactions to investigate the effect on the presence, absence, or combination of copper (I) and (II) catalyst, along with the formation of imines by use of starting materials with a fluorinated handle, which substantially improved the monitoring of the reaction. This research project began a mechanistic and selectivity study of how an imine could be synthesized in a novel manner from amines using phosphite reductants. However, the full mechanism was yet to be entirely elucidated and had unanswered mysteries surrounding phosphorus compounds that were unable to be detected by instrumental analysis.