Synthesis of Norcross Compounds

[maratsydney]

Hello everyone! My name is Marat Korsik, I started my PhD with @mattodd about two months ago. I am working on Series 4, in particular, I focused on the synthesis of “Norcross compounds” #390 . Below is my synthetic pathway with the references to my ELN (blue arrows indicate future plans).

Background of this work:

• Thomas Macdonald did the first work in this field in his Honours thesis in 2015.
• Tianyi Zheng and Haochuan Mao (exchange students from Nanjing University in China) made further progress in 2015 and 2016 respectively (Tianyi Zheng ELN+summary) (Haochuan Mao ELN)
• Most recently, @jaspert95 Jasper Tyler (exchange student from Sheffield University) contributed towards synthesis of “Norcross compounds”. (ELN+report as last entry). (#493)

• 519 @LachlanKlein from Griffith University is working towards the same goal on the similar compound (ELN)

Short term goals:

• Synthesize compounds VI-X
• Synthesize unsubstituted [1,2,4]triazolo[4,3-a]pyrazine for further investigation of core bromination

[MFernflower]

@maratsydney This is some fine work you are doing - I wonder if you could also explore an expanded ring system? I do believe 1,4-oxazepane is commercially available?

[MFernflower]

@maratsydney Regarding upping the yield of the Willamson I wonder if using Li-tetramethylpiperidide with a suitable solvent (PhCF3?) would increase room temp yields when combined with an improved work up procedure?

[maratsydney]

@MFernflower good point about 1,4-oxazepane will try to make it, talking about reaction MK003 the problem was in work up procedure. Now I am doing it again and it looks like yield is much higher , I will update on this later.

[MFernflower]

If you have the time could you post your synthetic plan to make 1,4 oxazapane?

A version of compound VIII that's missing the two fluorine atoms was shown to be totally inactive!

[maratsydney]

Here minor update: Confirmation of structure V was done by synthesis of previously made by @edwintse compound and comparing the NMR spectra, synthetic scheme shown below:

Also first post is updated.

[MFernflower]

@maratsydney Amazing work! - what was the point of the boronate coupling? Was it as a proof of concept?

[edwintse]

@MFernflower It was to confirm that bromination was occurring at the desired position.

[MFernflower]

@edwintse sorry I am not up speed but this means you can blast the naked tp core with NBS and get 5,3dibromo[1,2,4]triazolo[4,3-a]pyrazine out?

[maratsydney]

@MFernflower the idea of that scheme above to prove bromination in position 3 of compound IV, but I will try to play with naked core in the future.

[MFernflower]

To my untrained eye it looks like there could be a large potential for a run away reaction with the naked core and NBS Resulting in the core being halogenated in all possible positions - I assume for this reason temperature control is key?

(Sorry to bother with all the questions - I have no lab experience at all - I tought myself biochem]

[MFernflower]

@maratsydney i seem to recall somebody having issues with hartwig rxn that were solved by replacing BINAP with JohnPhos

[maratsydney]

@MFernflower thanks for your suggestion, it definitely worth to try different ligands.

[MFernflower]

@maratsydney If you have some spare time I'd be curious about the following four compounds - I chose them because I want to see how much we can get away with "distorting" the para-ochf2 position without loosing potency and because the boronic acids are commonly available!

[MFernflower]

@maratsydney I seem to recall from a few days ago that you had an issue coupling aniline to the bromo triazolopyrazine core - Have you tried proton sponge in MeCN ?

[maratsydney]

@MFernflower Thank you for comments, 1) I will probably make suggested compounds, but later since main focus is on C-N coupling.

2) Need to read about proton sponge, haven't heard about it before.

[maratsydney]

Update: Finally set of 5 Norcross compounds was made and it will be shipped very soon with the next batch to Dundee. After more than 10 ligands were tried in different conditions, best result showed JohnPhos (was suggested by @MFernflower). Important point in purification was switch to reverse phase chromatography that helped to achieve separation of dehalogenation byproduct from desired product. Although I manage to make it yields vary in a range of 2-5% and all attempts to improve it were unsuccessful. This reaction will be studied further in order to find a reason for such a low yield.

MK008-20 (1HNMR, 13CNMR, HRMS, ELN); MK048-1 (1HNMR, LRMS, ELN); MK049-1 (1HNMR, LRMS, ELN); MK050-1 (1HNMR, LRMS, ELN); MK052-1 (1HNMR, LRMS, ELN)

---

MK008-20 FC1=CC(CCOC2=CN=CC3=NN=C(N4CCOCC4)N32)=CC=C1F InChI=1S/C17H17F2N5O2/c18-13-2-1-12(9-14(13)19)3-6-26-16-11-20-10-15-21-22-17(24(15)16)23-4-7-25-8-5-23/h1-2,9-11H,3-8H2 BBKXHWRASNHAOR-UHFFFAOYSA-N

MK048-1 FC1=CC(CCOC2=CN=CC3=NN=C(N4CCC(F)(F)CC4)N32)=CC=C1F InChI=1S/C18H17F4N5O/c19-13-2-1-12(9-14(13)20)3-8-28-16-11-23-10-15-24-25-17(27(15)16)26-6-4-18(21,22)5-7-26/h1-2,9-11H,3-8H2 QEKAFCQAHVHCHN-UHFFFAOYSA-N

MK049-1 FC1=CC(CCOC2=CN=CC3=NN=C(N4CCC(F)CC4)N32)=CC=C1F InChI=1S/C18H18F3N5O/c19-13-3-6-25(7-4-13)18-24-23-16-10-22-11-17(26(16)18)27-8-5-12-1-2-14(20)15(21)9-12/h1-2,9-11,13H,3-8H2 XGYZBGPCRAEWAT-UHFFFAOYSA-N

MK050-1 FC1=CC(CCOC2=CN=CC3=NN=C(N4CCC(C(F)(F)F)CC4)N32)=CC=C1F InChI=1S/C19H18F5N5O/c20-14-2-1-12(9-15(14)21)5-8-30-17-11-25-10-16-26-27-18(29(16)17)28-6-3-13(4-7-28)19(22,23)24/h1-2,9-11,13H,3-8H2 VSNCNIYPDHLNGV-UHFFFAOYSA-N

MK052-1 FC1=CC(CCOC2=CN=CC3=NN=C(N4CCN(C)CC4)N32)=CC=C1F InChI=1S/C18H20F2N6O/c1-24-5-7-25(8-6-24)18-23-22-16-11-21-12-17(26(16)18)27-9-4-13-2-3-14(19)15(20)10-13/h2-3,10-12H,4-9H2,1H3 PXDXCQZMCIITIC-UHFFFAOYSA-N

[MFernflower]

@maratsydney Regarding the low yields I wonder if using a non-ionic base could help?

http://www.organic-chemistry.org/abstracts/lit1/097.shtm

I.E taking this procedure and swapping the xantphos for johnphos and the aryl Nonaflate for an aryl bromide

[maratsydney]

Biological activity data (for 5 compounds mentioned above) posted in #26 with the most potent compound (MK048-1) activity equal to 1.51 uM. Based on relatively low activity further exploration of the Norcross compounds is on hold. Closing issue.