The sequence shown in the diagram consists of two consecutive PTC reactions. The first reaction is a Michael addition that may be an I-Reaction that starts with the deprotonation of the methylene group of di-t-butyl malonate. The pKa of di-t-butyl malonate might be higher than the pKa of dimethyl malonate which is 13. As we teach in our 2-day course “Industrial Phase-Transfer Catalysis, “according to the Halpern pKa Guidelines, this Michael addition, may be on the border of I-Reaction and T-Reaction if the pKa of the methylene group of the malonate exceeds about 16. The carbanion (enolate) from the deprotonation attacks the double bond of t-butyl acrylate for the Michael addition.
Even if the pKa of di-t-butyl malonate is higher than that of dimethyl malonate by 1-3 pKa units, sodium hydroxide with PTC should be sufficiently basic to deprotonate the methylene group of the malonate without using so much excess hydroxide that it would cause hydrolysis of the t-butyl esters or the methyl iodide in the second step that is a PTC C-alkylation.
For that reason, we question the need for the expensive t-butoxide base which could be needlessly expensive.
The reaction was performed on a 1000-liter scale, so the price difference between NaOH and potassium t-butoxide could be significant.
The inventors chose THF as the solvent. Perhaps they had to use t-butoxide as base due to this choice of solvent. Had they chosen a more water-immiscible solvent like toluene, maybe it would have facilitated the use of a PTC-NaOH system if protection of the ester from hydrolysis was a key consideration.
The second step was a classical PTC C-alkylation that could probably have also used PTC-NaOH with a non-polar solvent. The alkylating agent was deuterated methyl iodide.
The overall yield was very good at 95%, so that was obviously good performance. Our questions relate more to the cost, especially the possibility to replace the combination of PTC and t-butoxide with PTC and NaOH.
When your company needs to reduce the cost of strong base reactions, you can both improve process performance AND reduce development time by integrating the highly specialized expertise of Marc Halpern at PTC Organics into your process R&D either through PTC Process Consulting or PTC Process Training.
