Nucleophilic aromatic substitutions are often performed at “high” temperature (60 C – 180 C) depending on the activity of the nucleophile and on the activation of the leaving group on the ring by electron withdrawing substituents. Mercaptides are good nucleophiles and require lower temperatures. Phase-transfer catalysis conditions further activate the reactivity of nucleophiles, though have limited effect on the inherent activity of the ring being attacked. PTC activates the already nucleophilic ethyl mercaptide anion to perform the reaction shown in the diagram at a very mild temperature, which is also useful to avoid hydrolysis of the thioester in the presence of aqueous base.
Interestingly, similar results were obtained by starting with the acid chloride (3,6-dichloropyridine-2-carbonyl chloride) as the starting material, also using TBAB as the phase-transfer catalyst. One equivalent of ethyl mercpatan made the thioester and the second equivalent of ethyl mercaptan performed the nucleophilic aromatic substitution. The inventors also attempted a non-PTC reaction using sodium hydride and the PTC-NaOH reaction worked better.
PTC Organics has helped companies achieve low-cost high-performance nucleophilic aromatic substitutions using phase-transfer catalysis. Now contact Marc Halpern of PTC Organics to improve you process performance and R&D efficiency when developing commercial nucleophilic aromatic substitutions and nucleophilic aliphatic substitutions.