Copper Mediated Photocycloadditions for the Synthesis of Small Heterocycles
- Author(s): Flores, Daniel Mark
- Advisor(s): Schmidt, Valerie A
- et al.
The 2+2 photocycloaddition of two pi components is advantageous for the synthesis of 4-membered rings due to the ability to rapidly generate molecular complexity from an atom-economical approach. However, these theoretically simple transformations are synthetically challenging due to mechanistic constraints. Despite the prevalence of these small carbo- and heterocycle rings there is a dearth of practical synthetic methodology for their synthesis
Drawing inspiration from the fields of Lewis Acid catalysis, photoredox catalysis, and the prevalence of copper in photocatalytic reactions we set out to develop new methodologies to fill the void. Early work focused on attempts at using various photosensitizers or preformed substrate-catalyst complexes to facilitate the desired cycloaddition. While these did not produce the desired cycloadduct these experiments offered valuable insight into the photochemistry of copper and our experimental setup.
Utilizing the tridentate scorpionate ligand trispyrazolylborohydride led to the successful development of a 2+2 carbonyl-olefin photocycloaddition (COPC) for the synthesis of oxetanes. Notably, this method engages alkyl ketones, which are more challenging to engage via direct irradiation pathways. The optimized system was also seen to work for the analogous Analogously, this method works for 2+2 imine-olefin photocycloadditions (IOPC) to generate azetidines with diverse functional group tolerance. Mechanistic investigations and single X-ray crystallography support the in-situ formation of a Cu-olefin resting state. Full molecule density functional theory (DFT) calculations indicate that upon irradiation this complex undergoes a MLCT that ultimately leads to oxetane or azetidine formation.
To further expand the scope of the 2+2 COPC and IOPC, we sought to utilize DFT calculations to rationally design ligands. A computational high through put screening method has been developed for evaluating the photophysical properties of various tridentate ligands bound to copper. While there are discrepancies with experimental data this enables a quick evaluation of the electronic transitions and an approximation of where they will occur. This has led to the rational design of several Tp derivatives as well as identifying Tm, Tmp, Tc, and trisphosphino as promising ligands. Moving forward these scorpionates will be synthesized and their corresponding Cu complexes evaluated as catalysts for the 2+2 COPC and 2+2 IOPC.