"Successful" dehydrogenation

03 Nov
Published by RyanPakula
rjp1-4-13pdt.dx123.78 KB
PZQbox-cdcl3.dx127.45 KB

The sulfur melt dehydrogenation,

was carried out, with 9.5% isolated yield of the desired product and 69.3% recovered starting material.  Other products (observed by TLC) were not found after the column.
I tried the above reaction again, on a 100 mg scale.  By TLC, the reaction was clean at 1hr when I turned off the oil bath (160ºC), but another TLC after cooling appeared to have many more side products.  This is a bit counterintuitive, so I'll have to figure out what happened.  Regardless, the product was isolated from a column (250 mL 30% EtOAc in hexanes, 250 mL 38%, 250 mL 46%), as was the starting material.  The other spots observed by TLC were not found.
Proton NMR of the product and PZQ are shown below.  If you want, the jcamp files can be downloaded by clicking on the attachments (viewed with JSpecViewer), or you can save a copy of the bitmap files shown here and view them a bit larger that way.  Please give us feedback about this system of displaying/sharing NMR spectra.
I also have been attempting to find conditions on the GC with which to monitor this reaction.  We believe using 1,2-dinitrobenzene as a standard should work, but it has to be able to withstand the 160-220ºC temperatures for prolonged periods without reacting with sulfur nor PZQ nor the product.  Any insight into this would be welcome, including whether reactions should be expected, or other standards that would be better.
Proton NMR of dehydrogenated product.  The jcamp is attached as "rjp1-4-13pdt.dx"

Proton NMR of praziquantel from the bottle.  The jcamp is attached as "PZQbox-cdcl3.dx"
The aromatic Hs integration is high due to presence of the chloroform peak.  Assignments are based on a 1998 Analytical Profiles of Drug Substances and Excipients paper, volume 25, page 463 (there's no DOI for this paper).



MatTodd's picture

Awesome, Ryan.
Can you also attach the original bitmaps to your post so we can see them in all their glory? The assignment of PZQ is odd, right, but confirmed by 2D NMR studies in the paper you mention. Geminal protons coming at such different chemical shifts...
Also, if we post raw spectral data let's try to get Chemspider to notice - just add "loadtochemspider" somewhere at the end of the post and it'll get picked up. Check out this previous post. You could also include the InChis for the relevant compounds.
The GC assay you are developing is a nice way to check the yields of this important reaction. Sulfur is inexpensive and the reaction is simple. Apart from the need for chromatography... If we could get the yield high, however, we can crystallise, making the route attractive.