There is nothing I hate more than not being able to draw a plausible mechanism for a seemingly simple transformation. (That is not entirely true; I hate coriander, jazz music and water-boarding too, but you get the point.)

Acid-catalyzed ring-contraction to thiazole

We have this reaction we know works, but I fail to get the curly arrows right. It bothers me a great deal. For a number of reasons, I cannot provide the exact structure or literature reference here, but the essence of the reaction is as depicted above. An acid-catalyzed ring-contraction to a (fused) thiazole in good isolated yield in gram scale. Several other functional groups are polite bystanders, suggesting relatively benign conditions. I feel somewhat confident that the first two steps must be an internal sulfur nucleophilic attack on the protonated imine followed by ring opening by water, and by all means do correct me if you think otherwise…

Bad mechanism

…but then what? The proposed acetal intermediate could maybe be hydrolyzed to its corresponding ketone, sure. However, that does not really help us much, does it? I am, frankly, completely lost.

Something appears to be fishy with the oxidation level. Agreed? No matter how I draw it, at some point a hydride or a carbon anion (God forbid under acidic conditions) is a leaving group, and I am no big fan of those. Alternatively, you could kick out the top ester, but that would involve the generation of carbon monoxide… ugh. While deformylation occurs readily in vivo, it does so rarely in the flask, in my humble experience. We have no oxidant in the mix (well we have air, if that helps). Also, if the top ester is the leaving group, why is the final compound an ester?

For the record, I have drawn even stupider mechanisms involving carbenes or nitrenes, but I hate them even more.

I need your help to understand this one. Feel free to use imgur or some other image provider, and post links below to pictures of better suggestions. Or just type it up. The correct answer, preferably! 🙂

I have great confidence in you. I know you can outperform me here. Do it! Thanks.


17 Responses to A plausible mechanism, please!

  1. KR says:

    I think your final structure is very close to the product. Under the reaction conditions, the protonated hemiacetal that you drew could be converted to a formyl group. At that point, you have a 1,3-dicarbonyl compound, which is perfectly set up for a retro-Claisen reaction (i.e. a deformylation). You do need an air oxidation to give the final product, but that seems reasonable under the reaction conditions. I always enjoy a good mechanism question!

  2. azmanam says:

    Here’s what I got so far. I’m teaching malonic ester synthesis today, so maybe I have that on my mind… But once I get to the aldehyde, I can’t see the rest of the mech… 🙁

    I agree, though, this seems like a net oxidation (two, if I’m counting correctly…) and that does seem odd under acidic conditions. Have you tried it anaerobically to see if it still occurs?

    • drfreddy says:

      I like your alternative beginning. Seems reasonable to me. Arrows bottom right hurt my eyes a little, though 🙂 Have to reproduce them on paper here until I deliver my verdict.

  3. aytchnu says:

    I like azmanam’s mechanism but the 1st step is an aza-cope ring opening instead of protonating the thioether

  4. aytchnu says:

    *I had/think its an aza-cope

  5. drfreddy says:

    I like the concept of a saturated ring oxidized by air to furnish an aromatic.

    Many variants lead to O-alkylated carbonyls, on that we agree. Not sure how to deal with those in a convincing way.

  6. milkshake says:

    the tautomer of your staring material looks very similar to leuco-form of methylene blue. Leuco (dihydro) methylene blue re-oxidizes back to phenothiazinium in air even at room temperature. I think the oxidized form of your starting material (with extra C=S(+) bond) hydrolyzes, ring-opens, ring contracts, the liberated carboxyl decarboxylates and the produced thioaminal oxidizes to benzothiazole. I have not made benzothiazoles by this method, but for example formation of benzimidazoles from o-phenylenediamine and aldehyde with a trace of bisulfite works very nicely

    • JBH says:

      That sounds simpler and very reasonable! I’m an undergrad and, misleadingly, simply finding ‘working’ arrows for the majority of our exam problems does the job 😛 I haven’t seen many examples of air oxidations in synthesis.

  7. Robert says:

    Above is the original reference for the transformation. Turns out the aromatic functional group is actually quite important, as it facilitates the decarboxylation by liberating the initial alcohol allowing water to attack and a simple hydroxyl group is put in it’s original place. Super cool!

    • drfreddy says:

      Snakes, just discovered I can only access the last six years of Synthesis online. Ironically, I have two own papers from 2002 there I can’t get hold of today. Could someone be so kind to email me the above article? I will update this comment as soon as first person does, so my inbox isn’t flooded 🙂

  8. Luis Sanchez says:

    Is there evidence of a decarboxylation (actual CO2 being formed)?
    To balance the oxidation states, perhaps the molecule released is not CO2 but a species at the same oxidation state as formaldehyde (formed via a retroaldol-like mechanism). Since the solvent is an alcohol and there is acid present, it would end up being ROCH2OR. Then, the mechanism would work great if we had an OH on the aromatic ring…

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