Org Prep Daily

September 17, 2010


Filed under: procedures — milkshake @ 7:27 pm

4-carbethoxy-3,5-dimethylpyrrole-2-carboxylic acid tert-Bu-ester 16.35g was dissolved in neat trifluoroacetic acid 85 mL and the solution was stirred at room temperature for 30 min (the mix turned Burgundy red with gas evolution [Note 1]), then cooled to +5 C on ice/water bath. Neat triethyl orthoformate 16.5 mL (1.6 eq.) was added and the mix was stirred at +5 C for 35 min, then concentrated on rotovap from ambient water bath to a small volume. The residue was diluted gradually with water addition, 300mL, the resulting slurry was shaken for 5 min and the precipitated ethyl ester intermediate was collected by filtration, washed thoroughly with water and dried by suction.

This intermediate ethyl ester was suspended in ethanol 150 mL, placed on a 120 C oil bath and stirred to complete dissolution. A solution of KOH 20g (pellets, 85%) in water 200mL was then added to the mix, the flask was equipped with a short-path distillation adaptor and the reaction mixture was distilled under a stream of nitrogen gas on a 120C oil bath for 90 min. (Only water distilled at this point and the ethyl ester hydrolysis was complete by HPLC, [Note 2] ) The reaction mixture was cooled, charcoal (5 spoons) was added and the reaction mix was then stirred on ambient water bath for 30 min, and filtered (the charcoal was thoroughly washed on Buchner funnel with water). The combined filtrates were acidified with addition of 6M HCl, the precipitated product was collected by filtration on a large Buchner funnel, washed thoroughly with water and semi-dried by suction. [Note 3]

The crude product was dissolved in EtOH (900mL) at reflux, the solution was allowed to crystallize at ambient temperature overnight (14 hours). The product was collected by filtration, washed with EtOH, dried by suction and on highvac. Concentrating the supernatants to a small volume (but not to dryness), diluting the slurry with ethanol 100mL and refluxing the mix for 30 min, then letting the mix to crystallize at RT overnight provided a second crop of a pure product. The combined yield was 8.32g (81% th, overall Y) of a light-tan crystalline solid.

1H (d6-DMSO, 400MHz): 12.12(s, 1H), 12.10(very br s, 1H), 9.61(s, 1H), 2.46(s, 3H), 2.42(s, 3H)

Note 1: The original procedure calls for the tBu ester deprotection/acid-promoted decarboxylation to be performed  at 45C/15 min. In my hands, running this step at ambient temperature (23 C) for 30 min provided a cleaner reaction mixture and a less colorful final product.
Note 2:  Performing the hydrolysis under a nitrogen blanket seems to improve the final product purity. Also, 3,5-dimethylpyrrole-4-carboxylic acids esters are rather sluggish to hydrolyze, probably because of the steric hinderance and pyrrole NH deprotonation. Distilling ethanol from the reaction mixture  accelerates the hydrolysis by increasing the mixture boiling point.
Note 3: The crude material is static and rather hard to crush when completely dry – it is best handled moist.


  1. I sense some bis-functionalization happening soon, with those two kind-of-orthogonal synthetic handles (acid and aldehyde). Have fun! :)

    Comment by HPCC — September 23, 2010 @ 12:15 pm

  2. It is the pyrrole aldehyde piece for making Sutent-like compounds

    Comment by milkshake — September 23, 2010 @ 3:41 pm

  3. The formylation (TFA/HC(OEt)3) looks pretty interesting, do you have any references to share? This is the first time I see this formylation.

    Comment by magnus — September 24, 2010 @ 7:08 am

    • I don’t have the original reference; apparently it is used widely for making pyrrole aldehydes – I have seen it in several porphyrine papers. I think it only works well for very electron rich substrates like pyrroles, and one has to follow the progress on the first run because it craps up easily – overreaction produces lots of yellow oligo- stuff. I think Vilsmeyer is somewhat cleaner but in this case the advantage is that one can do the formylation on one pot together with the tBu ester cleavage/decarboxylation.

      Comment by milkshake — September 24, 2010 @ 9:15 am

      • Just my two cents, but I wouldn’t be surprised if tBu ester cleavage would take place under Vilsmeier conditions… after all, there are 2 equivalents of dry HCl being produced under these conditions…

        Anyhow, in my experience, I dealt with a vinylogous Boc-amide, which, upon heating to 50C with 3 equivs of POCl3 in DMF, afforded N-Boc deprotection and enone chlorination…

        Comment by HPCC — October 18, 2010 @ 1:40 pm

  4. aldehyde preparation very nice

    Comment by Pratibha — November 12, 2011 @ 4:37 am

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