Proposed resynthesis strategy for TCMDC-123812 and TCMDC-123794

Published by pylioja on 18 August 2011 - 5:08am

Below is a proposed synthesis strategy to the two members of the TCMDC aryl pyrrole series. Please comment, give your thoughts and improvements.
Experimental attempts are documented on an electonic lab notebook found here: malaria.ourexperiment.org/tcmdc_ap/
Proposed synthesis strategy

Comments

MatTodd's picture

(Posting on behalf of a TSL member who emailed)
Have you tried toluene with lower temps than reflux?  If you need the heat I would go with a solvent like NMP and do the reaction in a sealed tube. Or try the reaction in a sealed tube with toluene. I always had better results with sealed tubes than with microwave. Just some simple modifications since you are getting product, but I would be concerned about the blue color change.

Darren Dressen, M.S.
Former medicinal chemist with Elan Pharmaceuticals
Chemistry teacher at Los Altos High School in California

Thanks for the input. It looks like it's working pretty well in a neat open reaction. The reaction is very clean and can be purified by a simple recryst. As for the blue colour, the HCl wash could be the cause. Whatever is causing it is only present in trace quantities as the NMR of the material was pretty clean. None of the subsequent samples have changed colour. If you have any further thoughts on the later steps, please get in touch. Any nice aldehyde to acid oxidations? I'm currently playing with permanganate oxidations and possibly chlorite oxidations. They seem to have the best precedent going for them.

Matt
I would suggest that, with the Vilsmier formylation, the mixture is aged at about pH 5 overnight after the quench; we have just been doing some large scale ones on an indole and the intermediate needs an overnight stir to fully hydrolyse. After basification and filtration, the yields are coming out close to quantitative.
 
Also, on the oxidation you may want to try peroxide/potassium carbonate in methanol which we have used with good results (though not on the above project).
Bill

Hi Bill, Thanks. I'll definitely give both of those a go.

Ref for the peroxide reaction is
Synthesis, 1986, 1024