Oxadiazole Synthesis

10 Oct
Published by Alice Williamson

The third round consultation highlighted compound Sf as an attractive target for synthesis.

 

We were delighted to hear from Professor John Wallis from the University of Nottingham Trent, who is hopefully joining the OSDD project and has expressed an interest in synthesising Sf. John will hopefully be posting soon, but he sent us a synthetic route towards which closely matched our plan (Scheme 1).

 

 

As Mat highlighted in his comment 1,3,4-oxadiazoles are also valid targets that 'in virtually all cases' possess log D values that are an order of magnitude lower than the corresponding 1,2,4-oxadiazole. Therefore, I am planning to synthesise the 1,3,4-oxadiazoles (Scheme 2) whilst John's group focus on the 1,2,4 analogues.

 

 

I'm currently synthesising the hydrazide and ideally I would like to acylate this with methyl chlorooxoacetate (i) as this would afford entry into ether, carboxylic acid and amido substituted oxadiazoles and decarboxylation of the acid could also afford the unsubstituted oxadiazole (Scheme 3).

 

 

Unfortunately, we don't have methyl chlorooxoacetate in the lab at the moment, so in the mean time I plan to work out the chemistry using acetyl chloride (iii), which should afford the 5-methyl oxadiazole. I could also try to use oxalyl chloride (ii) as an acylating agent and then chuck in a nucleophile in the hope that I can generate the relevant cyclisation precursor in situ. If this method works then Weinreb amides (as suggested by Paul Y) would provide a really useful handle for further derivatisation.

Comments

MatTodd's picture

Nice summary, Alice. Yes, I think it's an excellent idea we make both series, and that you and John are doing complementary work (yet you can learn from each other...). I also like your synthetic options at the end to access other derivatives with little extra effort.