Org Prep Daily

October 3, 2006


Filed under: procedures — milkshake @ 8:01 pm


3-hydroxy-5,5-dichloro-2,4-pentadienoic-acid-morpholide 2.875g (11.40mmol) was suspended in anh. dioxane 20mL under Ar and neat triflic acid 3.05mL (34.5mmol) was added. The mixture was stirred at 80C (oil bath) for 6 hours. The mixture was cooled, solid Na2CO3 4.1g was added with cooling on ambient bath, followed by water 40mL (CO2 evolution). The mixture was extracted twice with dichloromethane (2x150mL), the extracts were washed with brine 40mL, combined, dried (MgSO4) and evaporated. The solid residue was re-crystallized from a mixture of benzene 50mL and hexane 60mL. (The mixture was allowed to cool to RT, carefully decanted from a small amount of sticky gum, inoculated mechanicaly and allowed to crystallize for 12 hours at RT then in fridge at +5C overnight, 10 hours). The supernatants were decanted, the obtained light tan fluffy needles (1.737g) were washed with hexane and dried on highvac. Evaporating the supernatants and re-crystallizing the residue provided additional 270mg of pure product. Combined Y=2.007g (81.5%) of a light tan crystalline solid.

1H(d6-DMSO, 400MHz): 6.237(d, 1.7Hz), 5.402(d, 1.7Hz), 3.665(app t, 4.8Hz, 4H), 3.310(app t, 4.8Hz, 4H)


  1. What’s the driving force for this reaction? I believe that the reactive species is the keto tautomer of SM. TfOH is apparently an catalyst, then why is it used in 3 equivalents?

    Milkshake, thank you for sharing your nice work with us.

    Comment by MissingSnow — October 3, 2006 @ 8:28 pm

  2. I think the carbonyl protonation makes the conjugated C=C more electrophilic and eventually it closes on the carbonyl. But I don’t know. This procedure is from some lousy patent and they did not discuss the mechanism there. The cyclization was rather slow, you have to heat it to 80C, to make it go. In the original procedure, they called for refluxing the stuff in dioxane with large excess of concentrated perchloric acid and they were certainly no wussies – they did it on a big scale. I just replaced perchloric acid with triflic acid for safety reasons – and also because perchloric acid is quite expensive nowadays and it takes time to get it from Aldrich. (It has to come on a specialy-dedicated truck).

    Comment by milkshake — October 3, 2006 @ 9:03 pm

  3. are you suffering from an addiction to morpholine ;)?

    Comment by kiwi — October 3, 2006 @ 10:55 pm

  4. My superiors do – I have been trying to make something else but it has been difficult. To paraphrase Derek (and princess Leia): If it’s morpholines they want, it’s morpholines they’ll get.

    Comment by milkshake — October 3, 2006 @ 11:20 pm

  5. ta da! instant productivity… 😉

    Comment by kiwi — October 3, 2006 @ 11:47 pm

  6. Any tips for handling triflic acid? I need to add multiple portions of NIS to a reaction where triflic acid is the solvent, and was thinking of syringepumping in a solution (assuming it dissolves!) of NIS in triflic acid to the reaction overnight. Obviously, I’m afraid a polypropylene syringe might not survive to tell the tale.

    Comment by kjwx109 — August 6, 2009 @ 2:29 pm

    • OK scrub that. What are the chances of NIS surviving in triflic acid solution for a period of hours (he asks sarcastically). I suppose a better question is any suggestion for a solvent that will dissolve NIS (for the syringe pump addition), but will not react (once added) with the bulk triflic acid solvent?


      Comment by kjwx109 — August 6, 2009 @ 3:00 pm

      • I have done a reaction like this, I believe it was a iodination procedure from Olah and it was NIS and TfOH in DCM at low temperature. I remember NIS+TfOH combo is not stable at room temperature, it turns dark brown by iodine formation rather promptly. Since TfOH is supposed to activate NIS by protonation, I don’t think you can use any coordinating solvent, maybe not even THF so chlorinated solvents look like your only bet. What are you iodinating? Can you use iodine monochloride? – that one does not have solubility problem. Or mix up your substrate with NIS slurry in DCM at low temp and add TfOH in DCM to this mix by a syringe pump. Syringe pump comes with a glass syringe.

        Also, NIS in TFA as a solvent is quite powerful, and you can use it at room temp.

        I suppose you could also mix up TFA, NIS and your substrate at low temp and add BF3.Et2O to this mix slowly – TFA-BF3 complex is pretty acidic, I have been using it instead of TfOH for triethylsilane reduction of poorly reactive benzylic OH (because the TFA+BF3 mix was easier to work up in this case since TES-F is much more volatile than TES-OH).

        Here is one more (a completely ridiculous) suggestion: if your substrate can survive TfOH in refluxing DCM, you can load up NIS into a miniature Soxhlet extractor and let DCM to extract it and wash it down slowly into the react mix – instead of spooning NIS in there over time.

        Comment by milkshake — August 7, 2009 @ 6:38 am

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