At the beginning of every new process development project, we first do a literature search to see what similar reaction conditions have been chosen for similar reactions. Sometimes, we encounter procedures that scream out to be replaced by phase-transfer catalysis.
In the reaction shown in the diagram, the role of the catalytic iodide was to activate the alkyl chloride alkylating agent and the role of the phase-transfer catalyst was to transfer the phenoxide from the solid surface of the potassium carbonate and activate the phenoxide for the O-alkylation nucleophilic substitution.
In this case, we wonder why the inventors chose to use DMF as the solvent followed by chromatography for isolation when they clearly already thought of using tetrabutylammonium iodide to catalyze the reaction. The answer is that the inventors were probably not process chemists, they may have just been interested in obtaining material quickly and purifying it without any process development.
The inventors probably could have easily used a water-immiscible solvent and washed the salts away from the organic product before purifying the product and possibly may have avoided handling losses and solvent-entrainment losses which may be at least partially responsible for the 80% yield instead of a higher yield that we would expect from a PTC etherification of a phenol.
In this case, phase-transfer catalysis using a water-immiscible solvent is particularly applicable since the next step is a borohydride reduction and that too should be a PTC reaction.
So, if the inventors wanted to streamline their process and still insist upon doing chromatography after the borohydride reduction to obtain a pure product, they could have performed both the O-alkylation and the borohydride reaction in a PTC single-solvent one pot process without isolation of intermediates (just exchange the aqueous phase between reactions) then perform the separation by chromatography.
In fact, PTC-borohydride reactions in water at the right pH usually need to a lower excess of the expensive borohydride than when more conventionally performing such reactions in ethanol.
The inventors might have been medicinal chemists just trying to get product and not process chemists trying to optimize a process. This PTC Tip of the Month is directed at process chemists who find literature procedures and are responsible for developing them into practical processes that minimize cost in real world unit operations upon scale up.
Another example reported this month that begs to use PTC instead of DMF is the S-alkylation of 2-amino-4-chloro-benzenethiol with ethyl iodide in the presence of tetrabutylammonium iodide in DMF (see Example 14 in US Patent 9,567,304). They even used cesium carbonate as the base instead of potassium carbonate. What were they thinking?
Now contact Marc Halpern of PTC Organics to assure that you are developing viable PTC processes, not publishing procedures that look like you’re an academic chemist who can’t manage his/her supplies budget.
