Org Prep Daily

November 20, 2010

2-acetyl-3-ethoxyacrylic acid ethyl ester (E/Z)

Filed under: procedures — milkshake @ 7:13 pm

A mixture of ethyl acetoacetate 52.0g (399 mmol), ethyl orthoformate 59.2g (399 mmol) and acetic anhydride 81.6g (800 mmol) in a 0.5L round flask was refluxed under nitrogen on a 150 C oil bath for 90 min. The reflux condenser was replaced with a shortpath distillation apparatus and the formed ethyl acetate was distilled out from the reaction mixture at atmospheric pressure under nitrogen from a 150C oil bath. (This took additional one hour). The cooled reaction mixture was then distilled at 6 Torr from an oil bath (30 C to 90 C) to remove the formed acetic acid. The distillation residue was then fractionally distilled on highvac. After a small fruity-smelling front fraction (few mL) the desired product distilled at 75-82 C/0.25 Torr.

The obtained main fraction of the product was re-distilled on highvac, b.p. 80 C/0.15 Torr. Y = 48.2g of a colorless slightly oily liquid. The pure product has only a faint (non-fruity) odor.

1H-NMR (CDCl3, 400MHz) shows two sets of closely-spaced signals of the E and Z isomers, approximately of equal height:  7.671(s, 0.5H), 7.639(s, 0.5H), 4.251(m, 4H), 2.407(s, 1.5H), 2.346(s, 1.5H), 1.402(m, 3H), 1.339(m, 6H)

Note: A condensation of this material (2.5 mmol) with the diaminotriazole (2.0 mmol) from the preceding experimental in AcOH 5 mL at RT (10 min) and then at 110 C (for one hour) followed by evaporation and precipitation of the residue with MeCN provided the following cyclization product in 76% Y.
1H(d6-DMSO, 400MHz): 10.353 (s, 1H), 9.010(s, 1H), 7.774(app d, 8.8Hz, 2H), 7.423(app d, 8.8 Hz, 2H), 4.370(q, 7.1Hz, 2H), 3.084(s, 3H), 2.976(s, 6H), 1.368(t, 7.1Hz, 3H)

14 Comments »

  1. I’m curious about the regiochemistry in the cyclocondensation reaction. When acylating this type of diaminotriazole, the reaction occurs at the ring nitrogen. Would this imply that condensation onto the ketone happens first, followed by Michael addition/elimination? Or do you think the exocyclic amine does the conjugate addition first?

    Comment by Jere — November 22, 2010 @ 9:49 pm

    • Yeah, diaminotriazole acylation goes to the N1 ring nitrogen (I have done it on this substrate with benzoyl chlorides and arylisothiocyanates, in pyridine) – but for some reason when the cyclizations is performed in hot acetic acid the regioselectivity gets inverted and it is actually the NH2 that ends up reacting with the more reactive moiety of a bis-electrophile.

      I have seen a similar effect with 3,4-diamino-1,2,4-triazoles condensation with arylglyoxals where one can reverse the product ratio from 5:95 (in most solvents, protic and aprotic, polar and nonpolar alike) to 2:1 just by running the condensation in AcOH+pyridine mixture or with NaH2PO4 in methanol. I suppose mono-protonation has to do with the regioselectivity reversal.

      Comment by milkshake — November 23, 2010 @ 10:53 am

  2. I’m guessing 1,4-addition occurs first, because of the partial oxonium character that ethyl enol ether is bearing. If you push the electrons up into the carbonyl, then you see the ketone’s a poorer electrophile than the beta-carbon “down there”.

    Comment by HPCC — November 23, 2010 @ 1:42 am

  3. I have done preparation of analoguous (Z)-methyl 2-(methoxymethylene)-3-oxobutanoate from methyl acetoacetate and trimethyl orthoformate. The reaction is described in several papers, sometimes with quite high yields (e.g., OBC 2009, 7, 2182 reported 82 % yield). In our hands, we obtained about 60 % yield of pure crystaline compound as a mixture of E/Z isomers. However, we have also obtained some fractions containing an impurity (total estimated yield of 10-15 %), apparently with the same mw (MS). We failed to solve the structure by NMR of a fraction containing about 90 % of the by-product (the rest was only the required product). Have you observed formation of similar by-product?

    Comment by Stan — November 24, 2010 @ 9:54 am

    • I have not analyzed the reaction byproducts – I observed some lower-boiling front fractions during the highvac distillation that had a strong fruity odor, and so I have performed the second re-distillation quite carefully (and took a middle cut – and made sure the purified product did not have any extra proton signals).

      Under reflux with 2 equivs of Ac2O one can expect to get some C- and/or O-acetylation of acetoacetate.
      MeCOCH(CO2Me)COMe would be isomeric with your product.
      (With Et-acetoacetate/triethyl orthoformate/Ac2O the acetylated byproduct would be lighter than the ethoxymethylidene product, by one methylene unit – so if it happened in my prep, the byproduct would have probably distilled before the main product. Maybe that’s what the funny fruity-smelling front fractions were… )

      It would be easy enough to find out: ethyl diaceto-acetate is commercial and I bet Me diacetoacetate has NMR published somewhere. If it turns out that unwanted acetylation of the starting material is the origin of your impurity, perhaps one can combine trimethyl orthoformate with Ac2O first and sample the mix for GC or NMR to monitor the formation of (MeO)2CHOAc and (MeO)CH(OAc)2 – which are supposed to be the actual formylating agents in this reaction – and only later add Me-acetoacetate to the mix when there is less Ac2O around.

      I wonder though if anyone tried the prep with succinic anhydride instead of Ac2O – the succinoyl byproducts with a free CO2H should have rather low volatility – and one could possibly even wash the crude product after the first distillation with bicarbonate…

      Comment by milkshake — November 24, 2010 @ 1:30 pm

  4. What happens with that aminotriazole and methyl acrylate? Michael reaction to the non-ring nitrogen then acylation on the ring nitrogen?

    Comment by partial agonist — November 24, 2010 @ 10:34 am

    • I am not sure – I have not tried acrylate. (I think this particular piece behaves more like vinyl ether rather than acrylate). Maybe propiolate ester would be worth trying.

      Comment by milkshake — November 24, 2010 @ 1:08 pm

  5. Milkshake (or anyone else for that matter), do you have a good method for preparing silanized silica gel?

    Comment by PotStirrer — December 7, 2010 @ 4:30 am

    • No I don’t – I think I would rather buy it.

      Comment by milkshake — December 7, 2010 @ 9:22 am

  6. You should try this in a microwave reactor… did this at about 190°C for 10 minutes in almost quantitative yield… nice building block for pyridine or indole syntheses btw :)

    Comment by Heiko — December 13, 2010 @ 11:50 am

  7. Hi MS,

    I have a problem involving CF3 substituted 1,3 keto pyruvates in the pyridine ring formation. This particular substrates seems unreactive . I tried reaction in ethanol and I have been trying under basic conditions as well. What type of solvent or reagents help in the condensation reactions to form Pyrine ring systems.

    Thanks very much for the help.

    Marto

    Comment by marto — February 1, 2011 @ 2:12 pm

    • I don’t understand what you mean by “CF3 substituted 1,3 keto pyruvates”. (Pyruvate is MeCOCO2R)
      Maybe you can try trifluoroethanol or acetic acid as a solvent. Try both, maybe protonation can help to make the carbonyl more reactive.

      Comment by milkshake — February 1, 2011 @ 3:12 pm

  8. Will any one suggest the role of acetic anhydride in above reaction

    Comment by Harish — September 1, 2012 @ 3:07 am

    • the actual in situ generated formylation agents are supposed to be (EtO)2CHOAc and EtOCH(OAc)2

      Comment by milkshake — September 2, 2012 @ 10:00 pm


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