Org Prep Daily

January 23, 2010

2-formyl-5-methylpyrrole-4-carboxylic acid

Filed under: procedures — milkshake @ 9:57 am

D-glucosamine hydrochloride 6.470g (Acros; 30mmol) was suspended in methanol 100mL and tert-butyl acetoacetate 9.50g (60mmol) was added, followed by triethylamine 8.5 mL (61 mmol). The mixture was refluxed on a 80C bath for 1 hour with vigorous stirring. The reaction mixture was evaporated and the residue was dissolved in water (about 150mL) with potassium carbonate 2.8g (solid, 20 mmol) added. The mixture was extracted twice with ether (2x150mL) and the organic phases were back-extracted twice with additional water (2x150mL). [The organic phases were discarded]. The combined aqueous extracts containing the pyrrole product were transferred into a 1L beaker, fresh ether 100mL was added and the mixture was placed on ambient water cooling bath. With vigorous stirring, a solution of KI04 29.0g (135 mmol) in water (about 150mL) was gradually added over 15 min period with vigorous stirring (delayed gas evolution and foaming!).  When the potassium periodate addition was complete the mix was stirred for extra 30 min. More ether (400mL) was added and the mixture was shaken and separated. The aqueous phase was re-extracted with additional ether 200mL. The organic phases were washed saturated aq. sodium bicarbonate three times (3x250mL), combined, dried (MgSO4) and evaporated. The syrupy residue gradually solidified on highvac.

This crude tert-butyl ester-aldehyde (5.05g) was dissolved in neat TFA 60mL. After 30 min the dark mixture was evaporated to dryness. The obtained solid residue was suspended in water, the solids were collected by filtration, washed thoroughly with water on the Buchner funnel, dried by suction and then on highvac. Y=2.940g of a tan solid (64% overall)

1H(d6-DMSO; 400MHz): 12.384 (br s, 1H), 12.105(very br s, 1H), 9.405(s, 1H), 7.263(d, 2.5Hz, 1H), 2.454(s, 3H)


  1. An obvious sticking-out-like-a-sore-thumb application of retrosynthetic concepts, isn’t it … 😉


    Comment by EJ Corey — January 23, 2010 @ 10:41 am

  2. Is there a similarly nice easy way to make the dimethyl (Sutent-type) analogues? – By chance I was reading the old Sugen J Med Chem papers yesterday

    Comment by Ed — January 23, 2010 @ 11:25 am

  3. ps SAR wise, what is the difference between the monomethyl and dimethyl pyrroles? Some kind of selectivity advantage?

    Comment by Ed — January 23, 2010 @ 11:30 am

  4. Sure it can be used for making Sutent-like compounds but I don’t think they will not be very good – with that one methyl missing. There is actually quite a nice way of making the corresponding analog piece with the extra methyl by classic Knorr pyrrole synthesis – it is a three step procedure and it can be done on large scale. It is in the Sutent paper and also in the patent.

    Glucosamine here acts as aminomalondialdehyde equivalent. It comes from processing shrimp waste so it is pretty cheap. But my heart weeps for those ruined stereocentres.

    Also, please don’t use living people’s names as your moniker, especially not as a throwaway kind of joke, and especially not with EJC

    Comment by milkshake — January 23, 2010 @ 1:03 pm

  5. It’s like you’re Professor Snape, and this blog is your copy of Advanced Potions.

    Comment by Joel — January 23, 2010 @ 2:15 pm

  6. How do you manage to get your comments time-stamped before the actually time arrives?

    Comment by philip — January 23, 2010 @ 2:53 pm

  7. And he’s BACK! Yay milkshake, I knew you couldn’t leave your adoring fans in the dark for too long. Good to see you are doing chemistry as well, does that mean you have new labspace with which to pound away in?

    Comment by OrganicOverdose — January 24, 2010 @ 10:21 pm

    • no, this one is a fairly old piece. Like with all other write-ups here, this procedure is not proprietary (nor giving away active stuff that is being pursued by my ex-employers). By the way, I deleted your lastest comment because it was exceedingly dim. Please take it easy.

      Comment by milkshake — January 24, 2010 @ 11:00 pm

  8. Good to see u back. can u clarify my doubt. When alpha amino esters (amine protected as amide)undergo saponification with aq. alkalie is there any chace of racemization reported. Do we need only catalytic amount of alkalie or stoichiometric amount to drive the reaction to completion. Thanking you in anticipation.


    Comment by pashu — February 2, 2010 @ 12:12 am

    • Acyalted alpha aminoesters racemize under basic conditions, especially with phenylglycine, tyrosine and phenylalanine derivatives. I think racemisation-wise it would be safer for you to use a strongly-acidic hydrolysis – 6M HCl, heat and then evaporate, much the same way the natural aminoacids are isolated from protein sources. If you cannot use strong acid maybe you can use enzymatic method: for example penicillinase is very good at cleaving phenylacetyl protecting group off a variety of aminoacids and this reaction is used on industrial scale in manufacture of sensitive antibiotics.

      If neither of these two methods is viable you can try to use LiOH.H2O (4 equiv) in THF-water 1:1 and start 0C and gradually bring the reaction to 40-50C and maybe also add some hydrogen peroxide later once the ester is hydrolyzed off. (The LiOOH is a better nucleophile and somewhat less basic also. LiOH use can supress the racemisation problem but will not remove it entirely.) Also some acyl protecting groups like trifluoroacetyl and formyl fall off considerably faster under basic conditions but that depends on the substrate. The protected amino – is it primary or secondary? Is the carboxyester in alpha position to the acetamido?

      Comment by milkshake — February 2, 2010 @ 2:43 am

  9. The protected amine is tertiary and ester is in alpha position. sincere thanks for the support.

    Comment by pashu — February 2, 2010 @ 3:52 am

    • then I would definitely use formyl protection, you can employ mixed anhydride AcOCHO for the formylation – it works quite nicely in these cases

      Comment by milkshake — February 3, 2010 @ 4:13 am

      • thx dude

        Comment by pashu — February 8, 2010 @ 2:19 am

  10. Hi Milkshake,

    I have an off topic question about using MeOH in hydrogenations. I know I have heard that you can get methylation (of an amine?) but I can’t remember the specifics or any reference. THanks!

    Comment by Ryan — February 2, 2010 @ 2:25 pm

    • N-methylation of amines and self-ignition of vapors is a common problem with methanol + palladium +air combination. If you don’t deoxygenate your mix before throwing in Pd/C powder you can have a flame-up and you can generate formaldehyde which then produces N-methylated impurities because the Shiff base of your amine with formaldehyde gets hydrogenated. So use a good grade of MeOH for dissolving your product and get most of oxygen out by Ar sparge on sonicator or by couple vacuum/Ar exchanges before throwing in your catalyst.

      Also, I suppose Pearlman catalyst should be lot less prone to ignite MeOH or to generate formaldehyde in situ because this precatalyst is in its inactive form [as wet Pd(OH)2 on charcoal ].

      I rather like to do hydrogenations in ethanol or ethyl acetate – less fire risk. Please note that ethanol can also have similar problem (N-ethylation of amines) because acetaldehyde is naturally occurring in anhydrous EtOH but less so in 95% EtOH. So it is better to use 190-proof EtOH instead

      Comment by milkshake — February 2, 2010 @ 3:46 pm

      • Thanks a lot Milkshake.

        Comment by Ryan — February 2, 2010 @ 7:01 pm

    • Fu, X.; Cook, J. M. Journal of the American Chemical Society 1992, 114, 6910-6912.
      Fu, X.; Cook, J. M. Journal of Organic Chemistry 1993, 58, 661-672.
      “Debenzylation using catalytic hydrogenolysis in trifluoroethanol, and the total synthesis of (–)-raumacline”
      Patrick D. Bailey,* Mark A. Beard, Hoa P. T. Dang, Theresa R. Phillips, Richard A. Price, and James H. Whittaker. Tetrahedron letters 2008.
      These are some of the ref which talk about N- methylation of amine during hydrogenolysis/hydrogenation

      regards pashu

      Comment by pashu — February 3, 2010 @ 3:17 am

  11. Milkshake,

    You might have heard about our new contribution to Organic Chemistry released today: ChemSpider SyntheticPages. If not see:

    When we go to submission mode, as the present beta is read-only, I’d love to have you add your syntheses to the database. Each record will be DOI’ed and will be reviewed by the editorial board as well as by the community so these will be “micropublications”. I know this would add a burden on you to submit them there. Would you be willing to have us submit them on your behalf? Thanks

    Comment by ChemSpiderman — February 2, 2010 @ 11:42 pm

    • how about this idea – I will have my stuff posted here and if there is one procedure that you like I will send it to synthetic pages as well. By the way do not expect a stream of new procedures appearing anytime soon, as you have noticed I lost my job recently.

      Comment by milkshake — February 3, 2010 @ 3:14 am

  12. In the case of suzuki coupling, is boronic acid or the ester or the boroxines(anyhdride, trimer of boronic acid) or the oligomers is the most desired coupling partner. Normally many of the boronic acids are sold as mixture of anhydrides. Does the anhydrides have detrimental effect on the suzuki reaction. Or is there any way the equillibrium gets shifted toward boronic acid under the suzuki reaction conditions.

    Comment by pashu — February 8, 2010 @ 2:17 am

    • under reaction conditions the anhydrides revert promptly to boronic acid. Cyclic pinacolate esters are supposedly somewhat slower but personally I found no difference

      Comment by milkshake — February 8, 2010 @ 8:55 am

  13. Cute. I assume you wouldn’t recommend TFAing a pyrrole-2-carboxylate, right?

    Comment by LiqC — February 17, 2010 @ 10:01 pm

    • well its gonna decarboxylate in TFA, then the liberated pyrrole will turn into dark polymer… But if there is a second electron withdrawing group on the pyrrole ring it will live long enough in straight TFA so that you could either isolate it, or even throw in triethyl orthoformate and formylate it in situ in the 2-position.

      Comment by milkshake — February 18, 2010 @ 12:08 am

  14. Hi MS,

    I have an off-topic question, one reported procedure use arsenic acid for a skraup type cyclization. I would like to avoid this acid due to its toxicity. Is polyphosphoric acid is OK to use? Please suggest me any alternatives if you have any experince with such chemistry.



    Comment by marto — February 23, 2010 @ 2:16 pm

    • that must be some extremely old procedure. A very nice procedure using a modernized variant of Skraup from Chris Douglas group is here

      Comment by milkshake — February 23, 2010 @ 9:04 pm

  15. Thanks very much


    Comment by marto — February 24, 2010 @ 12:30 am

  16. Thanks for the procedure, Milkshake. I used it to prepare the ethyl ester of this acid, so I started with ethyl acetoacetate and stopped halfway, recrystallizing the product from CH2Cl2-hexane. The only two differences were that I did not back-extract with water and used NaIO4 for oxidation. The scale was one-half of your quantities and the yield was 60%. White crystals, 1H NMR (CDCl3, 500 MHz): δ 1.34 (t, J = 7.2 Hz, 3H), 2.63 (s, 3H), 4.29 (q, J = 7.2 Hz, 2H), 7.37 (d, J = 2.5 Hz, 1H), 9.39 (s, 1H), 11.08 (br.s, 1H); 13C NMR (CDCl3, 500 MHz): δ 13.5, 14.3, 59.9, 115.3, 124.5, 130.4, 144.0, 164.3, 179.2.

    BTW, the authors of Tetr. Lett., 39 (1998), 9271-9274 promise that the methyl group could be oxidized to the second aldehyde with CAN.

    Comment by J ♥ HC — April 24, 2010 @ 2:02 am

    • thank you for this comment – please have you seen any transesterification of the ethyl ester with methanol?

      Comment by milkshake — April 24, 2010 @ 9:28 pm

  17. Well, the honest answer is that it never came to my mind to check that, so I didn’t even run a TLC on the reaction mixture. Given that the yields are close, and the TFA hydrolysis might be near quantitative, and that I did not see any noticeable losses on crystallization – I would assume there haven’t really been any.

    Comment by J ♥ HC — April 27, 2010 @ 1:47 am

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