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Knoevenagel failure

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Babcock_Hall:
Some years ago we made a vinyl sulfone bearing two phenolic -OH groups using this reaction.  Generally we use pyrrolidine/acetic acid in one attempt and beta-alanine in the other.  Recently, we made a vinyl sulfone on a hydroxypyridine.  The starting materials were an aldehyde and a sulfonylacetic acid, and the yield was modest.  When we tried similar conditions on an isomer of the first hydroxypyridine, we keep getting extremely low yields, on the order of 1%.  In one instance a large amount of starting material was recovered  The second compound can form a hydrogen bond between the hydroxyl group and the aldehyde oxygen.  It occurred to me that this H-bond might make the Knoevenagel reaction slower.  Thoughts?

rolnor:
Yes, the aldehyde can be much less reactive. Did you get a lot of crap or was it just poor conversion? You could silylate the phenolic hydroxy maybe, just boil with BSA before the reaction and use water-free conditions. Or use NaH/TMSTriflate, you could then add more NaH for the condensation as soon as the silylation is ready, you can monitor this with GC

Babcock_Hall:
Hi Rolnor,

Thank you for your help.  The most recent attempt gave a very low conversion with much starting material remaining, but I am not sure about the attempt before that.  We could double the relative amount of sulfonyl donor in the Knoevenagel, but I think that will only be a marginal improvement.

We tried TBDMS and TBDPS protecting groups previously, and in at least one case, we lost the protecting group on silica.  I cannot remember what happened the other time.  I am considering going back to the Horner Wadsworth Emmons reaction once I identify a good protecting group.  I have a gut feeling that acetyl will not work, but THP has been suggested to me.  We have a little time to make this decision as we finish up some other work.

rolnor:
You should use a small PG, TMS is better I think, you can of course not isolate this but you can see on GC that you got the PG on the hydroxyl. THP is also a bit big I think, maybe a MOM (Metoxymethyl)group could work also. Horner Emmons is probably easier to control.

https://en.wikipedia.org/wiki/Methoxymethyl_ether

Babcock_Hall:
MOM would be perfect, except for the toxicity of the reagent.  We will work on other compounds and come back to this problem after I go back to Greene and Wuts...

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