This solid-liquid PTC reaction demonstrates several of the strengths of phase-transfer catalysis. First, the reaction is performed under very mild conditions at room temperature for only 45 min and gives 95% yield after isolation by chromatography.
Secondly, a quaternary carbon is formed under these mild conditions, so steric hindrance is not a barrier.
The base used was ground KOH. Grinding the solid KOH obviously increases the surface area of the available base and minimizing the water by using solid KOH reduces the amount of water available in the system that could hydrate the attacking enolate which could reduce its nucleophilicity. Thus, the combination of using solid KOH and grinding provides a particularly strong base under PTC conditions.
It is surprising that the inventors chose to use such a large excess of KOH (4 equivalents excess) since they already had a relatively strong base. In fact, the pKa of the acidic C-H of the beta-ketoester is about 10-11. Since the pKa of water is 15.7, the use of KOH may have been overkill and potassium carbonate might have been sufficient. In light of the pKa difference between the beta-ketoester and water, 1 equivalent of KOH should have been able to deprotonate at least 99.9% of the acidic C-H groups and maybe we would use a bit more KOH to absorb the 1 equivalent of water generated by the deprotonation in order to minimize hydration of the enolate (even assuming that the KOH was 85% with 15% water). Sometimes PTC chemists might choose KOH (MW 58 g/mole) or NaOH (MW 40 g/mole) instead of potassium carbonate (MW 138 g/mole) in solid-liquid PTC systems to minimize solids in PTC-base systems with organic substrates with a pKa of 10-11 or less. But by choosing 5 equivalents of ground KOH, they had a lot of solids, so we feel that the inventors should have at least screened K2CO3.
While this procedure could be optimized a bit, it is a good example of a high performance PTC C-alkylation to form a quaternary carbon.
Whether you need to optimize a PTC process or develop a new process to achieve low-cost high performance green chemistry using phase-transfer catalysis, now contact Marc Halpern of PTC Organics to benefit from the highest process performance while improving your R&D efficiency by achieving your goals in the least number of experiments.
Watch this video about how to improve R&D efficiency using phase-transfer catalysis.
