Update on TCMDC-123812 and TCMDC-123794: Oxidation issues

19 Sep
Published by pylioja

Subject 

Rants

In the last couple of weeks my time has mostly been spent trying to figure out whats going on in the oxidation of pyrrole-3-carbaldehyde to the corresponding acid.
Reaction Scheme PY3_5.png

  • NaClO2//sulfamic acid, Pinnick
  • KMnO4 in aqueous pyridine, acetone or THF/t-BuOH.
  • Oxone
  • TEMPO/bleach
  • Hydrogen peroxide/K2CO3
  • Jones

All of these usually gave starting material. Prolonged heating or multiple equivalents of oxidant was usually required to provide new products. In particular Pinnick oxidation appears to give the cleanest conversion to a new product (PMY 3-8), however the 13C NMR data does not correllate with the expected product nor does the 1H NMR integrals. More likely, they hint at some kind of dimeric structure. Mass spectrometry hasn't matched anything that I could make out so far. It could also be that the acid is just hiding underneath, I may need to attempt taking this material through the side-chain coupling and see if anything resembling product comes out. It really should be possible to do this oxidation, the product acid is available from several compound libraries and preparation of analogues have been mentioned in a patent (WO2006076202)[Edit: Also WO2011075684 mentions using the acid purchased from Enamine] using permanganate in reasonable yield.
I've also had a go at a Friedel-Crafts approach to access the ester analogue. This would be a nicer approach and may be worth pursuing further. Anyone have a feel for how to make this happen?
Reaction Scheme
Another potential way round the oxidation problem is synthesis of the core with the ester already attached as for our alternative strategy. We were mostly avoiding this due to the use of α-haloketones that are not all that pleasant. Nevertheless I'll give this a go.
In happier news, Laura has made the phenyl and p-tolyl analogues of the pyrrole, both with good recrystallisations. She'll move onto the formylation of these next as well as the synthesis of the p-CF3 analogue.

Comments

MatTodd's picture

Every year I teach undergrads that oxidations of aldehydes is straighforward. "Generally very difficult to stop at the aldehyde" I say, in a lecture about alcohols "because the aldehyde is very reactive, and goes on to the acid". Lecture material - meet reality.
Naturally the aldehyde could be electron rich because the pyrrole is pi-excessive, but with those methyls there, I wouldn't even expect the aldehyde to share anything with the pyrrole. Obviously we're sure that your aldehyde is the aldehyde and not already the acid...

Yeah, according to the literature data for that compound and our MS, it does seem like it's the right stuff. Unless the literature is wrong but I doubt it for this... 9.85 ppm is perfectly reasonable for the aldehyde and less likely for the acid. Also extractions with base do not pull the material out of organic, so I'm fairly confident that it's not the acid. I don't think the salts would be that organic soluble.