The patent cited in the diagram uses tetrabutylammonium iodide in several examples for etherification using either DMF or NMP as the solvent. One may speculate that polar solvents were used due to the high polarity of the amino isooxazole products after hydrolysis.
The use of tetrabutylammonium iodide suggests that the etherification is catalyzed by rapid in-situ formation of the more reactive alkyl iodide, though most of the PTC etherifications reported in this patent were performed at room temperature, so iodide co-catalysis may not have been required. If this reaction were to be optimized for scale up, one would use tetrabutylammonium bromide and KI, both at levels much lower than 10mole% which would save on the cost of the catalyst.
The price of iodine and iodine derivatives fluctuate significantly over time. The price of tetrabutylammonium iodide is usually set at the highest historical cost of iodide. Moreover, quats like tetrabutylammonium have a much higher affinity for iodide than for bromide, typically 100 times more or higher. For these reasons, we usually use tetrabutylammonium bromide in combination with KI since KI is rarely at the historical high of iodine price and TBAI is formed from TBAB and KI in-situ to an overwhelming extent.
It is not known if the inventors screened less polar solvents that would form two phases with water and make workup a bit easier, if scaled up. The reaction was reported on a small scale (~2 mL) and more than 90% of the reaction mass was DMF. Even though the isooxazole reactant is quite polar, the ion pair with the quat as the phenoxide may be amenable to PTC in a less polar solvent. This is important because the final isolation of the intermediate was by chromatography which should usually be avoided. PTC in toluene may facilitate this possibility.
Additional similar TBAI-catalyzed reactions were reported by the same group in US Patent 9,296,711 on March 29, 2016.
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