Differentiation of Boron Reagents within Chan-Evans-Lam Oxygen Methylation

Methyl ethers have unique properties that make them impactful on biological molecules and medicinal drug synthesis. The current synthetic methodology focuses on using electrophilic methyl sources such as diazomethane, TMS-diazomethane, methyl iodide and dimethyl sulfate. These reagents pose a health risk to the scientists working with them due to their toxicity, even causing the death of a scientist in 2008. The Chan-Evans-Lam oxidative cross coupling reaction allows for the synthesis of methyl ethers while avoiding toxic electrophiles. This is done by pairing an oxygen or nitrogen nucleophile with a nucleophilic boronic acid using a copper catalyst and an oxidant. Chan- Evans-Lam oxygen arylation is well established using arylboronic acids, but there is limited precedent for oxygen alkylation. The Gorin Lab has published two papers on Chan-Evans-Lam methylation, one focused on carboxylic acids and the other on phenols using methylboronic acid. Other nucleophilic alkyl boron reagents have been used in cross coupling reactions such as boroxines, boronic esters and trifluoroborates. Methyl boronic forms of these derivatives are available in the forms of trimethylboroxine, 2,4,4,5,5-pentamethyl-1,3,2-dioxaborolane, and potassium methyl trifluoroborate. Using the optimized conditions from the previously published phenol paper1, conditions were developed for the substitution of methylboronic acid with these methyl boron derivatives. Because these new boron reagents have different properties than methyl boronic acid, these new reagents were tested on the N-heterocyclic phenol, 4-(pyrdine-2-yl) phenol, to see if previous yields could be improved and utilize the lessons learned in the optimization conditions. Initial troubleshooting for the use of these new derivatives on the carboxylic acid methylation conditions was done using 19F NMR.