Phase-transfer catalysis excels in thousands of reactions in dozens of reaction categories, but none is as successful as PTC etherification in terms of high probability of success when developing the application. Nevertheless, it is rather rare to see PTC etherifications of tertiary alcohols. Such an O-alkylation was reported in a patent that was issued last week.
The alcohol was bound to a carbon in an azetidine ring that was also bearing a phenyl group. The hydroxyl was deprotonated by 4M NaOH (~ 14% aqueous NaOH). This NaOH concentration is surprisingly low relative to most typical PTC-NaOH etherifications of alcohols (not phenols) that often use 50% NaOH of solid NaOH or KOH. Perhaps that it is the reason that such a large excess of NaOH was used. The low concentration of NaOH may have been needed to avoid side reactions, though tert-butyl esters are typically stable to concentrated NaOH.
Methylene chloride was the solvent and used in large quantity of 50X relative to the starting material, so the reaction was quite dilute. When using PTC-NaOH in the presence of methylene chloride, one must always be aware of generating formaldehyde. In addition, methylene chloride can act as an alkylating agent itself and create “methylene bridged” impurities. Given the report of quantitative yield, methylene bridging was apparently not observed.
TBAB is the most common phase-transfer catalyst used when screening lab reactions and it was used in this case. The alkylating agent was benzyl bromide and was quite effective when used in excess of 3 equivalents. Bromide was the leaving group and bromide was the counterion of the PTC quat cation, so there was no co-catalysis effect. In fact, it is possible that the use of a small co-catalytic amount of KI could have provided the opportunity to reduce the temperature, time or excess benzyl bromide by forming a small amount of benzyl iodide in situ (use less KI than TBAB).
Even though we would likely choose somewhat different PTC process conditions, especially if the reaction needs to be optimized for a commercial process, it is still notable that quantitative etherification of a tertiary alcohol has been reported.
If your company wants or needs to achieve low-cost high-performance green chemistry, especially for strong base reactions, now contact Marc Halpern of PTC Organics to integrate highly specialized expertise in industrial PTC-OH applications with your process development or process optimization goals.
