Proposed C-H functionalisation project for Massey University undergraduates

[thomasfallon]

Dear OSM,

I teach a 3rd year class at Massey University (Auckland campus), and we’re hoping to contribute to this fine project. This is one idea. Comments, criticism, and alternatives are very welcome.

The premise would be to demonstrate sequential C-H functionalisation on the unsubstituted triazolopyrazine core using some contemporary methodology. This might be a nice way to access new compounds for triazolopyrazine series, and would introduce students to some old and new reactions. It also raises interesting reactivity and regioselectivity questions.

The plan would be to make trazolopyrazine from pyrazine in four steps. From there, the class would be split into three groups, to work on three C-H functionalization approaches.

Palladium Catalysed Arylation: The report by Huestis (doi: 10.1002/ejoc.201301802) on the sequential arylation of imidazopyrazines using aryl bromides offers a great looking method, and a pretty close analogy to the triazolopyrazine system. The first arylation is a little different, but the second arylation is a pretty close model. It’s interesting to see complete C5 regioselectivity in this reaction.

Baran’s Minisci-type chemistry (doi:10.1021/ja1066459 and doi:10.1038/nature11680): Here we’re thinking about the arylboronic acid method, and the alkyl sulfinate method. These reactions should work, but regioselectivity is an open question. I suspect that C3 will always react first (not sure), but getting selective for C5 afterwards could interesting. On this point, Xiong has developed a predictive model for heterocycles including azabicyles (doi: 10.1039/c4ra01853b), but not yet applied to triazolopyrazine. Anyone interested in assessing this method, and running a few calculations?

The aim of this class project would be to show selective C3/C5 functionalization using a combination of these methods. Hopefully, this would include the option of placing an sp3 group at C5. If this could be done using the sulfinate chemistry, it might offer an alternative to current C5 alkylation strategies?

The synthesis of the triazolopyrazine should be good robust chemistry, and we might also prepare a few alkyl sulfinates. It’s a small class, and we won’t have much time for C-H method development. We would just take the best reported conditions, and have a go.

What do you think? Would this be useful? Thomas

[TrentWallis]

On a practical level, you can buy the 2-chloropyrazine so that might buy you some time to spend looking at other things?

[sdebbert]

My undergrads are using that Baran alkyl sulfinate chemistry to try to get 2-trifluoromethyl-4-hydroxymethylpyridine, for the synthesis of the sulfide/sulfoxide/sulfone targets laid out last winter. Crude GC-MS has shown useful selectivity for C2 over C3 (3:2 or better), but we haven't had much luck separating the one from the other.

Preparation of the alkyl sulfinates is pretty straightforward (if not especially cheap). I had a class of 40 use the Zn(SO2CF3)2 on ethyl isonicotinate, and saw a very wide range of conversion to product (as in, 5% to nearly 100%) under ostensibly identical conditions. I've got a summer student doing that chemistry right now, and will have her post her data toward the end of the summer. We also had decent luck using phenylboronic acid to arylate ethyl isonicotinate selectively at the 2 position in the same class with the Baran prep.

Honestly, I've been trying to talk my students into trying exactly the C-H functionalization of the parent bicycle you're describing -- I think it's a great idea. In the past, my students have really struggled reproducing literature preps for 5-chlorotriazolopyrazine from 6-chloro-2-hydrazinopyrazine. I'm interested to see if you have better luck making the parent (and I would definitely buy the 2-Cl-pyrazine, probably from Matrix). I agree that you should see pretty high selectivity for C3 and then C5 with the sulfinate chemistry.

[MFernflower]

@thomasfallon Really cool stuff!!! However I would consider buying about 100g? of 2-chloropyrazine from your favorite New Zealand chemical supplier

[thomasfallon]

Thanks for the advice and warnings. I'll definitely buy in the 2-chloropyrazine, and won't treat the precursor synthesis as trivial. Stephan, the sulfinate chemistry sounds a little inconsistent. I wish your student luck with this, and any further advice will be welcome.

[MFernflower]

@thomasfallon You can also buy the difluoromethoxy right hand part: http://www.sigmaaldrich.com/catalog/product/aldrich/553425

[alintheopen]

Hi @thomasfallon I love the plan and thanks for your input @sdebbert. An iterative C-H activation strategy for the synthesis of the S4 compounds would be really neat!

One other possibility would be to pick up on some of the work by @tyzhengsydney Haochuan Mao and @tscmacdonald (see #413). Perhaps some of the class could start from a 'naked' triazolopyrazine and some could start with the chorine handle?

One paper from my PhD group might be of interest too, Fionn also worked on the Baran chemistry detailed above. http://onlinelibrary.wiley.com/doi/10.1002/anie.201500067/abstract

[sdebbert]

Thanks for the link @alintheopen -- it's always cool to see these new-ish C-H activation methods used on large scales like that. I agree that it'd be worth looking at both the parent triazolopyrazine and the chlorinated analog.

[mattodd]

Hey @thomasfallon - have you formulated a plan for your class now, or are there remaining things that you could use some input on here? We can close this issue if you're done, to remove it from the To Do list, though the content remains available at the same URL. Would be interesting to know how you're faring in any case.

[mcoster]

Hi @thomasfallon - how did things go with your 3rd years and their direct C-H functionalisations? Looks like a really nice plan.