There are several interesting choices of reaction conditions for the reaction shown in the diagram.
Potassium carbonate was successfully chosen for this reaction. This suggests a rather acidic pKa (10 or less) of the methylene group activated by the ester and nitrile of the ethyl cyanoacetate. The potassium carbonate likely also served as desiccant to avoid hydrolysis of the ester.
The nucleophilic aromatic substitution of the bromide on the pyridine ring must have been sufficiently activated by the electron withdrawing group in the 2-position to be displaced at 90 deg C. It is not uncommon for nucleophilic aromatic substitutions to be performed at significantly higher temperatures, especially with the bromide located in the 5-position to the pyridine nitrogen.
The phase-transfer catalyst chosen was the standard tetrabutylammonium bromide. The tetrabutylammonium cation is not effective for transferring carbonate into any organic solvent, but it is effective in transferring the carbanion (enolate) of deprotonated acidic methylene compounds into almost organic solvent and activating the nucleophilicity of the anion for effective nucleophilic attack.
Indeed, the procedure reports that the reaction mixture was a suspension, which is not surprising due to the potassium carbonate and potassium hydrogen carbonate byproduct.
That begs the question, why did the inventors choose DMSO as the solvent? The phase-transfer catalyst could transfer and activate the carbanion (enolate) from the solid phase into a non-polar phase such as toluene that does not solvate the anion = not interfere with the nucleophilicity of the carbanion.
Of course DMSO is a good solvent for the reaction. But the workup used large volumes of aqueous phase and extractant solvent (ethyl acetate) before recrystallization to isolate the product.
The yield was not reported so we don’t know the extent of the handling losses from the workup that often result from choosing DMSO as the solvent. This is likely an important issue in this process since the is the first reaction of five reactions in the sequence and yield losses in early stages require a lot more starting materials to achieve the final product in sufficient quantity.
The inventors obviously were familiar with phase-transfer catalysis because they chose to use TBAB. It is always puzzling why chemists use PTC with DMSO instead of using PTC with a classical water-immiscible solvent that makes workup easier.
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