Progress on the resynthesis of TCMDC-123812 and TCMDC-123794

02 Sep
Published by pylioja

Subject 

Request for Help

This is the first biweekly-ish update on the resynthesis of TCMDC arylpyrrole series leads TCMDC-123794 and TCMDC-123812

So far the synthesis is progressing reasonably well. Our current approach is to form the pyrrole core via a Paal-Knorr cyclisation of 2,5-hexanedione and 4-fluoroaniline. This step is now well established (PMY 1-6) and has been tested on 100 mmol scale in 79% yield in a direct-drop process. Synthesis of two analogues of the pyrrole core has been started by an undergraduate student, Laura White. The Paal-Knorr step again seems robust although purification of these analogues may require some chromatography. The formylation again, is quite reliable but the latest and largest attempt (PMY 2-3) did see a significant drop in yield. For future analogues the aldehyde stage is a reasonable branch point, particularly if the ester functionality is not desired in the near neighbour analogues, but for the moment the oxidation of the aldehyde is our main concern. Room temperature permanganate and chlorite oxidations have thus far only given partial conversion to a new product by NMR. Use of oxone resulted in an different product as did prolonged heating in permangate. TEMPO oxidations and elevated temperature permangate oxidations in presence of base are to be evaluated shortly. If anyone has a great method for oxidations of pyrrole-3-carbaldehydes then please comment! If anyone else feels like making the aldehyde, it's perfectly sensible in a day. The Paal-Knorr is mostly complete complete in about 6-8 hours and doesn't really require purification of you don't want a nice solid. The Vilsmeier-Haack takes an hour so you could have a go yourself and tell us if the methods work.

 

Comments

Hi Paul,
Ahamed here, nicely written. I think for aldehyde oxidation you can try catalytic Lewis acid and H2O2 (or oxygen balloon). Hope this works.

Hi Ahamed, do you happen to have a reference for that? I've just tried one peroxide oxidation so far that only gave SM, but that was without lewis acid. It would be nice to use peroxide or some other nice oxidation procedure. The Pinnick I'm trying now is looking less promising with the latest NMR (not up on the lab book quite yet, received 10 mins ago). I might need to go for chromium oxidation just to get some compound pure so I know which compound to go after on purification. Nothing looks quite right by NMR at the moment and MS is not giving anything useful either. Cheers.

Hi,
I vaguely remember doing this sometime back in industry. I think it is CoCl2 and 30% H2O2 excess in toluene at about 60-70 degrees. It can take more than 24 h, so nice reaction to start on friday night. If i find my notes, i will send it to you.
Cheerios.