Abstract View

The upregulation of monoamine oxidase (MAO) enzymes has been implicated in early on-set Alzheimer’s Disease and present as potential positron emission tomography (PET) imaging targets for studying disease pathophysiology. Current synthetic approaches for accessing MAO-PET substrates utilize a 4-step sequence to derivatize pyridines, limiting modularity and access to 3-dimensional heterocycle fragments. To expand access to these imaging agents, herein we report the palladium-catalyzed cross-coupling of phenols with aryl and vinyl pseudohalides. Under optimized conditions, a TrixiePhos-ligated Pd species proved to be the most effective catalyst for forging biaryl ethers from aryl triflates and phenols. Within this system, electron-rich phenols perform best as nucleophiles and poorly as aryl triflates; conversely, electron-deficient phenol performed best as triflates and poorly as nucleophiles. By simply swapping the ligand to tert-butyl BrettPhos, the same conditions could also be utilized to readily accessible vinyl triflates to generate vinyl ethers. This ligand swap allows for direct access to a wide array of vinyl ethers bearing semi-saturated heterocycles with good to excellent yields (up to 90%). The main limitation of this methodology is the doubling of catalyst/ligand loading between the aryl and vinyl variations of the reaction. Overall, we have identified conditions for a general palladium-catalyzed cross-coupling of phenols and triflate electrophiles, enabling general biaryl ether synthesis and as well as ready access to new MAO enzyme inhibitors for applications in PET imaging. Future endeavors include developing a coumarin and complex saturated nitrogen heterocycle library to ¹³C radiolabel and assessing enzyme inhibition using fluorescence-based assays.