It is always nice to report an effective PTC reaction performed by one of our long-time loyal readers of the PTC Tip of the Month. Dr. Zofia Komsta is one of the inventors on this patent that uses phase-transfer catalysis to perform a C-alkylation of dimethyl malonate.
The pKa of the methylene group of dimethyl malonate is about 13. The first pKa of carbonic acid (base strength of potassium carbonate) is 10.3. PTC conditions activate the basicity of bases such as hydroxide and carbonate, especially in the presence of non-polar solvents, such as toluene chosen for this C-alkylation. Therefore, potassium carbonate was an effective base in this reaction.
In addition, potassium carbonate serves as a desiccant in case water is present in the system or is generated during deprotonation (in this case KHCO3 is the byproduct of deprotonation, not water). So, the use of potassium carbonate was a good choice for basicity, to activate the enolate due to no hydration and to minimize potential hydrolysis if water would be present.
We are somewhat surprised by the very long reaction time, but that was likely due to the fact that these reaction conditions were chosen for a single attempt and the process was not at all optimized. Dr. Komsta also suggested that there might have been some steric hindrance at work even though the bromide is secondary since the bromoalkyl group is near a multi-ring steroid.
It is very reasonable to assume that if this reaction was to be optimized for a commercial process, the mole ratios would be significantly reduced for the dimethyl malonate, potassium carbonate and the phase-transfer catalyst, relative to the bromoalkyl steroid.
It is noteworthy that Dr. Komsta performed her graduate research under Professor Makosza who was a pioneer of he use of quaternary ammonium catalysts for C-alkylations, first published in 1966, as we teach in our 2-day course “Industrial Phase-Transfer Catalysis.”
When your company needs to develop low-cost high-performance green chemistry reactions using base, now contact Marc Halpern of PTC Organics for PTC-base consulting. Dr. Halpern has been performing PTC C-alkylations since 1976.
