Phase-transfer catalysis excels in simple high yield procedures for the mono-C-alkylation of diactivated methylene groups in the presence of esters such as malonates, acetylacetonates and acetoacetates, avoiding hydrolysis of the esters.
The use of carbonate as base avoids premature hydrolysis of the esters in the acetoacetate ester reactant and the ethyl bromo propionate ester reactant shown in the figure. Carbonate is basic enough (pKa 10.3) to deprotonate the methylene group of acetoacetate (pKa 10.7).
Tetrabutylammonium iodide is used as a dual catalyst with the tetrabutylammonium cation being the phase-transfer catalyst and the iodide being the Finkelstein catalyst to activate the bromide. A cost-saving alternative to using expensive TBAI is explained in our 2-day PTC course. For commercialization, it is reasonable to assume that phase-catalyst loading of much less than 20 mole% could be used.
It is likely that the use of phase-transfer catalysis together with the iodide co-catalyst enables performing this reaction at room temperature which further reduces side reactions such as dialkylation and hydrolysis.
A possible reason for using less than one equivalent of ethyl bromo propionate and adding it dropwise at 0 C might have been to avoid dialkylation, so working at lower temperature is usually good for selectivity to minimize undesired side reactions.
The large amount tetrabutylammonium salts might have been at least partially separated from the product by water extraction but that is not clear since the amount of water used in two steps in the workup was not specified.
Now contact Marc Halpern of PTC Organics to learn how to maximize process performance and R&D efficiency for base-promoted reactions using phase-transfer catalysis through PTC Training (in-house or in Prague Oct 15-16, 2019), PTC Process Consulting or PTC Contract Research.
