Example 23 of this patent describes the reaction of the thiosulfonate anion with a secondary bromide in high yield. We have not seen this particular nucleophile in the PTC literature, but it is not surprising to see any sulfur nucleophile work well with phase-transfer catalysis. In this case, complete conversion was achieved, then 88% yield after chromatography. The substrate was a glycoside and this reinforces the notion that PTC works with secondary alkyl halide reactants. Example 23 uses a glucopyranose. Example 24 uses a galactopryranose. While acetonitrile was used as the solvent, we speculate that other solvents more suitable for commercial processes could be chosen.
There is one more interesting note from a process chemistry standpoint that should not be lost. In the next step, this intermediate is reacted with ethane thiol and a stoichiometric amount of triethylamine to produce a disulfide in what appears to be a nucleophilic attack by the ethanethiolate anion.
If we were developing a commercial process for these two steps, we would perform a one-pot 2-step reaction using PTC for the first reaction shown in the diagram, then add an inexpensive base, such as potassium carbonate, to deprotonate the thiol and perform the substitution. This would avoid the use of triethylamine which would need to be recovered and be replaced by an inexpensive inorganic base. Carbonate (pKb ~10) should be basic enough to deprotonate the thiol (pKa ~ 11) especially under PTC conditions.
We speculate that a suitable solvent could be found for both PTC reactions and that TBAB would also be suitable as phase-transfer catalyst for both reactions. If so, then the solvent could be designed to be immiscible with water (e.g., MIBK if we needed a polar solvent) and at the end of the first reaction, we would separate off the salts into an aqueous phase at room temperature and carry the organic phase forward to the second reaction. In this way, perhaps isolation of the intermediate could be avoided and not suffer from the additional handling losses and processing time. If successful, we would perform chromatography after the second step instead of after both steps. We don’t know that this would work, but as process chemists, this would definitely be screened if a commercial process development project were undertaken.
If you or your company can benefit from achieving higher process performance in a shorter development time for this PTC reaction or any other reaction, by having access to the best PTC expertise available, NOW CONTACT Marc Halpern to inquire about using phase-transfer catalysis to achieve low-cost high-performance green chemistry. Remember, PTC excels in thousands of reactions in more than 30 reaction categories including strong base reactions, nucleophilic substitutions, oxidations and reductions!
If you’re not sure if PTC can help your reaction, now fill out the PTC Project Evaluation Form and E-mail a scanned copy to Marc Halpern or send it by fax to Dr. Halpern at +1 856-222-1124. If your company does not have a secrecy agreement with PTC Organics Inc. already in place, please use “R-groups” instead of the exact chemical structures.
