GU Project 4: Synthesis of the Heterooxadiazole

[mcoster]

Outline
GU Project 4 will focus on synthesis of "the Heterooxadiazole". I'd prefer to just call it the oxadiazole, but to avoid confusion we'll stick with that name!

Note: we will be getting familiar with the chemistry via the 4-chlorophenyl series (from 4-chlorobenzaldehyde) until our order of 4-(difluoromethoxy)benzaldehyde arrives.

Our plan is heavily based on that proposed for the "Heterooxazole" in GHI #462, involving C-H arylation of the oxa(dia)zole. This paper suggests a Pd catalysed, silver-assisted process with the oxadiazole may be feasible. From what we can see, this differs from previous approaches that proposed formation of the oxadiazole by condensation of a triazolopyrazine ester with an amidoxime (GHI #448, #463).

The project is being undertaken by Tian, who is completing the fourth year of his degree at Griffith University as part of a collaboration between GU and Nanjing University of Chinese Medicine.

Links:
AEW 85-x
EGT 24-2, EGT 25-6
Synthesis of 3-phenyl-1,2,4-oxadiazole and C-H arylation thereof - Adv. Synth. Cat. 2017, 359, 772-778.
ArCl -> ArI using CiI, KI, DMI: Patent WO 2011111423
ArCl -> ArI using NaI, AcOH, H2SO4, MeCN: Tetrahedron 1998, 54, 9701-9710.
Haverford Superlab ELN1
Haverford Superlab ELN2
Previous synthetic planning - #448, #463
Earlier discussion of Griffith Uni OSM contributions - #508
OSM Desirable Compounds Not Yet Synthesised (DC-NYS)

Files:
Tian - synthetic plan.zip

Strings:
"Heterooxadiazole" (R = OCHF2)
InChIKey=HFPKPTYSFARKAA-UHFFFAOYSA-N
InChI=1S/C20H12F2N6O2/c21-20(22)29-14-8-6-13(7-9-14)18-26-25-16-11-23-10-15(28(16)18)19-24-17(27-30-19)12-4-2-1-3-5-12/h1-11,20H
FC(F)OC1=CC=C(C=C1)C1=NN=C2C=NC=C(N12)C1=NC(=NO1)C1=CC=CC=C1

[drc007]

You could make the reverse oxadiazole by displacing the aryl iodide with cyanide, then convert to amide oxime.

[mcoster]

Thanks @drc007 - unfortunately oh&s around cyanide use and storage is very prohibitive at my university these days, and will be particularly hard to get the required support for undergrad project students to use it, so we'll leave that approach for another group. Good suggestion though!

[drc007]

Shouldn't undergraduate lab training be about learning how to handle, reactive, air sensitive, toxic chemicals safely? So when they go into a lab they know how to work safely?.

[mcoster]

Completely agree! I still think it would be possible to do so, just lots of obstacles to jump over. Unfortunately, cyanide use and storage (and even benzene!) here requires a license from Qld Health. We formerly had a license holder within the building, but that lapsed and was not renewed due to lack of use.

[mattodd]

Nice route @mcoster and nice lit chemistry there. I'm interested if that works. Even getting to good quantities of the chloro core and the oxadiazole would be important so that you and others can perform the cross-coupling campaign.

[drc007]

I agree a stock of the chloro (or iodo) core would be very valuable, perhaps also look at making the boronic acid? Could open up lots of interesting cross-coupling chemistry.

[mcoster]

We just had Nicholas Meanwell give an incredibly useful workshop on three topics: i) fluorine in med chem, ii) bioisosteres, and iii) toxicology. During the second topic, he presented some comparisons of different heteroaromatic scaffolds. A takeaway message for me was that 1,3,4-oxadizoles often have better properties than 1,2,4-oxadiazoles. An example he presented showed analogous compounds where the former was more soluble and had lower logP than the latter. Sorry, don't have my notes here with me right now for details.. It does make me wonder whether a 1,3,4-oxadizole should be an even higher priority target than the current 1,2,4-oxadiazole:

Thoughts?

[mattodd]

That takes me back. Your comment has triggered a buried memory that @alintheopen had the same thought in the Series 1 project, described here. Looks good to me!

[drc007]

I suspect publication is worth mentioning
http://pubs.rsc.org/en/Content/ArticleLanding/2012/MD/c2md20054f#!divAbstract

[mcoster]

Nice paper - here's a few more. I have Nicholas Meanwell's excellent notes in front of me now. On a slide titled "Isosteric Deployment of Heterocycles", he references the following articles:
TJ Ritchie et al. Drug Discov. Today, 2009 14, 1011-1020
Ibid, 2011, 16, 164-171
TJ Ritchie et al. MedChemComm 2012, 3, 1062-1069
C Wermuth Ibid, 2011, 2, 935-941
Boström et al. J Med. Chem. 2012, 55, 1817-1830

[MFernflower]

@drc007 @mcoster It would be epic if we could made and test all three ring systems!

[mcoster]

Tian finished working on this project in October. He was able to synthesise the chloro 4-(difluoromethoxy)triazolopyrazine, however, the one attempt to convert this compound to the corresponding iodide was not successful. Issue closed.