Diversification of Triazolopyrazine Core Through Halogenation (TSP project)

[jaspert95]

My name is Jasper Tyler, I'm an exchange student from Sheffield University doing my TSP on the Open Source Malaria Project.

Description of Need: The current synthesis of OSM Series 4, the triazolopyrazines, involves a linear sequence which necessitates an early stage decision on the group on the triazole ring.

A more divergent approach would be the initial synthesis of a halogenated heterocyclic core, followed by sequential nucleophilic displacements (Route 1, below). These could be used to synthesise the current OSM Series 4 frontrunners as well as the “Norcross compounds” suggested by Neil Norcross of the Drug Discovery Unit, Dundee.

Initial work
The initial work in this area was laid out by Thomas Macdonald in his thesis
Haochuan Mao also made progress in his project in 2016 (#413 ) but suffered drawbacks from poor conversion rates, difficulty in purification of the core and unwanted products in the subsequent coupling reactions.

What I'm doing

• So far, the 5-chloro-[1,2,4]triazolo[4,3-a]pyrazine has been successfully synthesised and characterised with NMR, IR, mass spec and melting point.
• Efforts to chlorinate the triazole position were unsuccessful due to the lower activity of NCS compared to NBS.
• Using NBS, the brominated core was obtained at a comparable yield to different attempts with a high purity. Full characterisation will be performed.
• Currently I am screening various catalytic conditions for the halogenation reaction from literature reports of effective C-H functionalisation reactions of aromatic heterocycles.
• Using Pd(OAc)2 and AuCl3 as catalysts, no product was isolated from the reaction although small amounts of conversion were observed. Major product isolated from the AuCl3 reaction is suspected of being the brominated pyrazine core.
• 4 other catalytic conditions will now be tested in an attempt to improve the yield of halogenation.

[MedChemProf]

@jaspert95 Looks like some valuable work you are doing. You may have already seen the posting, but I just in case, I wanted to bring your attention to issue #487 . The palladium coupling we used was far from optimized, but it at least did give us some of the desired products. The links to the experimental details are in the issue posting.

[MFernflower]

@MedChemProf I wonder if swapping from xantphos to spanphos would increase product yield during step 3 of the norcross route? Bite angles are pesky pesky things!

[MFernflower]

@jaspert95 I am not a lab chemist. But I have came up with a few ideas to try regarding the chlorination of the mono-cl core. @mattodd Mind taking a quick look to see if this would work?

[jaspert95]

Update

• Finished halogenation catalyst screening. No conditions were found to improve yield from initial conditions.
  

• Poor conversion in the original method is due to a competing reaction to form the doubly brominated species
  

• Identity of the doubly brominated core was determined using mass spec and 2D NMR. This has been isolated and will now be fully characterized.

• Next week I will begin trying to displace the bromine for piperidine using various conditions.

• I'm also looking into substitution of the monochlorinated core and subsequent activation and coupling of the second position at a later stage. As this is an alternative route for divergent synthesis that also can be used to access the 'Norcross' compounds
  

• First reaction has been successfully performed with a yield of 79%

• Bromination reaction failed. Will repeat under milder conditions to detect conversion

[mattodd]

Nice summary @jaspert95 . Careful with the word "failed". You mean you didn't get the desired product, but it helps us to know if you regained starting material or not, since that can dictate what changes you make next time you run the reaction. I think in this case you obtained evidence that the conditions were too harsh, because your crude mixture appeared to contain degradation products of the expected material but no starting material. Hence your suggestion of making the conditions less harsh, or briefer?

[mattodd]

That di-bromo, mono-Cl core is actually quite a thing if one is interested in the rapid synthesis of diverse, functionalised heterocyclic cores. Not a priority, but it'd be very nice if that molecule were reasonably stable under ambient conditions and we could make a gram or so.

[mattodd]

Useful predictive tool that's relevant to this synthetic branch: http://pubs.acs.org/doi/abs/10.1021/acs.joc.6b00584, alerted via http://proteinsandwavefunctions.blogspot.com.au/2017/01/prediction-of-regioselectivity-of.html

[MFernflower]

"Next step is to write this up and get the set-up and analysis code in such a shape that we can distribute it. I've also started thinking about how to make the approach more generally available and usable for non-experts. A grant proposal is also in the works, so if we're successful that should definitely be possible to achieve." seems like that tool is not going to be usable for a while @mattodd

[mattodd]

Jan Jensen predicts bromination of the mono-chloro core where we expect it.

He can repeat on any SMILES relevant to this issue. Am suggesting the simpler core lacking any Cl/Br (Jasper 2) (C12=NN=CN1C=CN=C2) and the compound in the new strategy with an ether chain pre-installed (Jasper 3) (C12=NN=CN1C(OCCC3=CC=CC=C3)=CN=C2)

[MFernflower]

I'd be curious to see what the yield is if you try to chlorinate "jasper 3" at room temp using TCCA and PhCF3 as the solvent

@jaspert95 @mattodd