Org Prep Daily

August 16, 2007

So many carbonyls, so little use

Filed under: mechanisms — milkshake @ 4:12 pm

carbonylz.gif

Lately, I have been enjoying the pleasures of 3,5-diketoesters. The effort turned out to be a complete waste of time. But the joy of cyclization – priceless. 

4 Comments »

  1. Hi MS,

    I have been struggling to prepare high purity ,3,5 dioxo-hexanoic acid ethyl ester from dehydroacetic acid. After the completion of reaction using metal ethoxide as base and toluene as solvent (reaction conditions optimized), mixture was added to a dil HCl solution to quench the reaction and followed by extraction with toluene resulted in a crude product with 94% GC purity.

    Use of undistilled 3,5-dioxo hexanoic acid ethyl ester resulted in poor conversion in the Aldol reaction. I suspect that some acidic or related impurities could be present in the mixture that could affect the next stage (Aldol reaction). Please suggest some work up ideas so that isolation yield can be improved.

    Further purification by vacuum distillation resulted in low recovery of the final product with not much improvement in the purity (Could obtain only 30% from crude – residue material contains some inconclusive materials).

    These compounds having active methylene groups are quite base sensitive and the next reaction with aromatic aldehyde also problematic. I have generated trianion (NaH/THF – best conditions till now – aim is to react the terminal carbanion with aldehyde – LDA/BuLi as bases were not efficient) and treated that with aryl aldehyde to get the Aldol product. This reaction is also moderate yielding (60-65%) with quite a few side products. The isolation of the desired product from the mixture is also problematic due to the presence of similar impurities.

    Please suggest how the yield can be improved.

    Thanks

    Marto

    Comment by marto — December 15, 2011 @ 5:11 am

  2. I don’t understand your description of what are you trying to do: 3,5-diketohexanoic acid ethyl ester has two reactive methylenes. And also the methyl. Are you trying to do a condensation on one of them selectively? What kind of aldehyde are you trying to condense – and what are the products do you hope to obtain from it?

    Comment by milkshake — December 15, 2011 @ 6:39 pm

  3. sorry for the unclear query.

    I am trying to make 2,4 diketo hexanoate (ethyl ester) from dehydroacetic acid. We follow a literature
    method using metal ethoxide as reagent. The crude product after the reflux in toluene/ethanol is only with ~ 50% HPLC pure.
    along with lot of minor impurities (we cant conclude on other impurites due to the very less concentration)

    Vacuum distillation of this crude resulted in loss of product along with only slight improvement in purity.
    Column chromatography also did not improve the purity and recovery of the mataerial from the crude.
    There is also a stability issues with this compound at higher temperature (> 110 °C).

    It would be really helpful if you could give your insights for yield improvement and purification issues.

    We need to develop a scale up method for this transformation (~ kg scale)

    Thanks

    Marto

    Comment by marto — January 25, 2012 @ 7:49 am

    • I have not done any similar reaction like this myself but from the first look, the starting acetylpyrone (dehydroacetic acid) looks troublesome and ethyl ester of 3,5 diketohexanoic acid definitely looks like an unpleasant compound to purify and to even analyze/characterize – because of of the formation of various enol forms and the ease of self-condensation. Presuming that the literature method is not a bullshit (how old is the procedure – do they have NMRs?) I would go back to the published procedure and try to re-optimize the dehydroacetic acid ethanolysis conditions so as to get the best quality of crude product, because as you described the product purification is hard to do and the impurities will interfere in later steps.

      I would definitely start with making my own ethoxide from Na or K metal (unlike methoxide, the commericial Na and K ethoxide comes brown from oxidation/decomposition), I would use non-denatured biology grade of ethanol, or a grade for electron microscopy (most common EtOH lab grades come denatured with methanol plus isopropanol 5+5% or with methylisobutylketone) and I would distill it before use and throw away the front fraction (fronts may contain acetaldehyde).

      Also what are the methods that you use to characterize the Et-3,5-diketohexanoate purity? GC might not be ideal (because nonvolatile impurities do not show up) but HPLC and NMR are probably not good either because depending on the solvent used the various enol forms of your product might be stable enough on HPLC, NMR to separate and look like impurities with a different retention time or signals with different frequencies in 1H spectra – I have seen exactly this problem with commercial benzylester of acetoacetic acid from Fluka (the 95% AcAcOBn from Fluka looked like crap on HPLC and NMR, the apparent impurity profile did not improve much even with careful fractional distillation – but then I found out that the “impure” material was actually looking rather good on TLC – one spot – and the subsequent reaction with this “mixture” gave the expected product in high yield. Then I realized the impurity I was trying to remove was actually the enol form of the acetoacetate plus a tiny trace of benzyl alcohol).

      I would suggest that you run LC/MS on your crude diketohexanoate – and if you see the same M+1 value on several peaks on LC/MS and only one spot on TLC, the chances are that the various HPLC peaks in your “impure” material are just keto and enol forms of the same stuff.

      Comment by milkshake — January 25, 2012 @ 12:09 pm


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