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Knoevenagel failure

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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?

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

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.

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.

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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