Inducing regioselectivity in metal-bound aryne reactions and using ligands to govern divergent reaction pathways

Abstract

The highly reactive nature of arynes has been leveraged to make many value-added species. Despite this success, synthetic applications of aryne methodology remain limited by regioselectivity challenges. Additionally, regioselectivity issues can be especially prohibitive in metal-mediated aryne reactions as now additional interactions of the metals, ligands, and substrates contribute to regioinduction. Investigating regioselectivity of metal-bound arynes is crucial to expanding aryne methodology as some transformations can only occur through metal-mediated processes.To induce regioselectivity in metal-catalyzed aryne reactions, we postulated that ligands could be used to control the binding and subsequent functionalization of the aryne. To test this hypothesis, we used a palladium-catalyzed aryne annulation originally developed by Larock and coworkers as a model reaction. We found we can induce regioselectivity by using an unsymmetric (C1) monodentate ligand environment. Bulky monodentate phosphine ligands such as tri-tert-butylphosphine (PtBu3) gave the best combination of regioselectivity and yield. This system was compared to a symmetric (C2) ligand system that Larock and coworkers found optimal. Through these studies we provided the first evidence that ligands can be used to intentionally induce regioselectivity within aryne reactions. To further explore the origins of regioselectivity, we explored the molecular parameters responsible for regioselectivity via linear free energy relationships (LFER) and multivariate linear regression. To study how steric encumbrance influences regioselectivity, we performed Charton analysis on the aryne substituent and the ligand. These results showed that the ligand can amplify steric effects of the aryne substituent to increase regioselectivity. To study electronic effects, Hammett parameters of the aryne substituent were investigated and from these studies it was found that inductive effects influence regioselectivity. Having decoded the contribution of steric and electronic effects on regioselectivity independently, we next sought to create a more comprehensive regioselectivity model via multivariate linear regression. This model shows that both while both steric and electronic effects influence regioselectivity, steric encumbrance is a larger contributor to regioselectivity. Additionally, the mechanism and elementary steps of the catalytic cycle of the palladium-catalyzed annulation were investigated. Kinetic studies show aryne generation is the turnover-limiting step of the catalytic cycle. Upon testing the generality of this regioselectivity inducing approach in other aryne systems, we discovered that two operative pathways can occur to generate carbazoles within a palladium-catalyzed annulation reaction. Additionally, these reaction pathways can be controlled by the identity of the ligand. By using CataCXium® A as ligand, we can force the o-boryaryl triflate substrates to undergo a cross-coupling pathway rather than an aryne pathway.