Development of a Chromane-Forming Heck Reaction: Bisphosphine Mono-Oxide Mediated Regioselectivity Perturbed by Solvent-Based Peroxide Formation
Adrian Doggett, Michael Hay, Shane McKenna, Eric M. Saurer, Sarah E. Steinhardt, Yichen Tan, Christopher R. Wilbert, Steven R. Wisniewski
Abstract
The development of an exocyclic-selective, chromane-forming Heck reaction is reported. Detailed mechanistic studies revealed the crucial role of a bisphosphine mono-oxide-based Pd complex to promote high exo:endo alkene selectivity (>99:1) in the Heck reaction. Low levels of NMP peroxide in NMP (reaction solvent) can impact this selectivity by overoxidizing the ligand to bisphosphineoxide and promoting catalyst decomposition. The resultant colloidal Pd facilitates isomerization leading to significant levels of the undesired endocyclic alkene (>10%). A second-generation process is therefore developed to mitigate the risk of peroxides in NMP.