As we deal with COVID-19 there is a lot of talk about using quinoline-based structures for treatment. A patent was just issued this month that describes the synthesis of quinolone-3-diarylethers with higher water solubility for better oral absorption than some of the quinoline-based alternatives being considered.
The alkylation of the quinolone starting material shown in the figure proceeds preferentially at the oxygen instead of the nitrogen. This is enhanced by several factors as we teach in the 2-day course “Industrial Phase-Transfer Catalysis” when we discuss how to increase alkylation at the more electronegative atom of an ambident anion. In this case, the oxygen is more electronegative than the nitrogen. If water were present, it would hydrate the oxygen more than the nitrogen and block O-alkylation. Since the inventors used 2 equivalents of potassium carbonate as the base (that generates 1 equiv of potassium bicarbonate), it avoids the use and generation of water (it is a desiccant) and that enhances O-alkylation. Similarly, the inventors used “anhydrous DMF in a flame-dried flask” that again assures the absence of water.
The use of a tetrabutylammonium salt means that the cation that spends most of its time near the more electronegative oxygen, forms a looser ion pair with the oxygen that further enables O-alkylation.
The use of the polar DMF solvent assures an even looser ion pair between the tetrabutylammonium cation and the oxygen anion.
The iodide of tetrabutylammonium iodide likely forms iodomethyl ethyl carbonate in situ from the chloromethyl ethyl carbonate and that likely reduced the energy of activation of the alkylation so the reaction temperature could be 60 deg C.
It is possible that the inventors could have used catalytic tetrabutylammonium salt and if this process would be commercialized, using catalytic amount of PTC would surely be screened during development. We would also likely be able to significantly reduce the excess of the alkylating agent during optimization before scale up.
By the way, when I spent a couple of years in the Sinai Desert in the early 1970’s, I was required to take chloroquine periodically to protect against malaria.
Also in the 1970’s, I alkylated acridone and we obtained quantitative O-alkylation and no N-alkylation, using dimethyl sulfate as the alkylating agent.
When your company needs to perform ambident alkylations and you want to achieve low-cost high-performance green chemistry, contact Marc Halpern of PTC Organics to integrate our highly specialized expertise in ambident alkylations with your company’s process development and optimization goals.
