The PTC N-alkylation shown in the first step in the diagram contains a characteristic that may be surprising to many of you who took the 2-day course “Industrial Phase-Transfer Catalysis.” This characteristic is that tosylate was successfully used as the leaving group. In the famous page 76 of every PTC course manual in the past 20 years, tosylate is shown to have a very strong affinity for the quat, about 500 times more than chloride. This affinity for tosylate is so strong that tosylate can often be a catalyst poison. In those cases, tosylate should be replaced by mesylate as the leaving group since mesylate has an affinity toward the quat 5 times LESS than chloride.
The reason that tosylate works well in this case is that the anion that is formed in the reaction that is competing with tosylate for association with the PTC quat is an organic N-anion that contains 11 carbon atoms. Therefore, in this reaction, the quat has no problem pairing with the N-anion in the presence of tosylate due to the high organophilicity of the N-anion.
The use of carbonate as the base suggests that the pKa of the indole N-H, that has electron withdrawing assistance from the adjacent ester, is low enough to be deprotonated by carbonate.
The choice of phase-transfer catalyst was appropriate, though if one wants to save some money, tetrabutylammonium bromide would likely be sufficient unless the bromide would attach the alkyl tosylate and cause it to be less active.
Water was added during workup between the N-alkylation step and the hydrolysis step with aqueous NaOH. Separation of phases was performed after adding the water, presumably to separate the potassium tosylate before the hydrolysis step, but no further water washes were performed before the 50% NaOH. Therefore, it is not known if the tetrabutylammonium tosylate was present during the hydrolysis or of was mostly removed during the phase separation. The reason we mention this is that it is possible that the phase-transfer catalyst assisted in the hydrolysis, though it is still unlikely because the affinity of the quat toward tosylate is roughly 50,000 times higher than the affinity of the quat for hydroxide.
PTC excels in N-alkylation. When your company needs to achieve the lowest cost highest performance N-alkylation, now contact Marc Halpern at PTC Organics to inquire about highly specialized PTC Process Consulting or PTC training to improve process performance and R&D efficiency using phase-transfer catalysis.
