The September 2022 PTC Reaction of the Month is rather unusual. My first thought when seeing the reaction is that there must be a mistake since it looks like a ring contraction that somehow losses two methyl groups covalently bound to a quaternary carbon atom and appears to be a PTC carbene reaction due to the presence of a phase-transfer catalyst, chloroform and 50% NaOH that are classical PTC carbene conditions.
It turns out that the reaction diagram is NOT mistaken and in fact, the inventors performed this reaction many times, screening many catalysts and they found the following order of phase-transfer catalyst activity:
TBAB > 18-crown-6 > MTBAC ~ TBA OH > 15-crown-5 > TBAC > Aliquat 336 ~ BTMAC >>> no PTC
I was so baffled by this reaction (even though baffles were not involved!) that I reached out to my friend and excellent process chemistry consultant, Dr. John Studley of Scientific Update, who is one of the inventors on this patent. John referred me to the article: Lai, J.; Westfahl. J.; J. Org. Chem. 1980, 45, 1513-1514, that provides the speculation for the multistep mechanism for this reaction. We refer you to the original article for the details and diagrams of the proposed mechanism.
The proposed mechanism starts with the addition of the trichloromethide ion, NOT dichlorocarbene, to the carbonyl carbon of the piperidone followed by epoxide formation (the O-anion displaces one of the chlorides of the added CCl3 to form a dichlorooxirane) which undergoes a series of rearrangements, a dehydration, an intramolecular N-acylation (to form the pyrrolidone ring) and the elimination of acetone to form the product shown, in up to 83% yield (determined in solution, not isolated yield, with complete conversion of starting material) in as little as 2 hours.
For those of you counting, the carbon atom balance involves the addition of one carbon from chloroform and the elimination of 3 carbon atoms of acetone for a net loss of 2 carbon atoms. If any of you can think of a more plausible mechanism than that proposed, please share your thoughts. Personally, I am impressed with the creativity required to propose so many movements of electrons and my IQ is insufficient to have predicted the outcome shown for mixing tetramethylpiperidinone, chloroform, NaOH and a phase-transfer catalyst.
I also wonder why TBAB worked better than any of the other catalysts screened. I speculate that it is likely related to forming a bromodichloromethide that eventually reacts faster downstream than the intermediates from trichloromethide. None of the other phase-transfer catalysts screened contained a bromide ion.
By the way, the original JOC article cited, included the addition of 1 equivalent of piperidine to the reaction mixture to achieve more complete conversion of an intermediate to the final product, 5,5-dimethyl-3-methylenepyrrolidin-2-one, however the procedure in this month’s patent shown in the diagram, did NOT use the addition of piperidine.
As you loyal readers know, I usually end the PTC Reaction of the Month blog post by urging you to contact me at PTC Organics, but in this case, please contact John Studley at https://www.scientificupdate.com/consultancy/. Why? Because John understands this reaction and I never would have guessed any of this!
