The Aussies - unexpected products from substitution down under

[david1597]

Posting on behalf of @maratsydney, @edwintse and myself following discussions with @mattodd (and others through GH) over the last couple of days:

Credit to @alintheopen for naming 'The Aussies'.

Background

Marat has identified an unexpected product, unequivocally shown by a crystal structure, in which the nucleophile has attached at the 8-position rather than 5-position during the final synthetic step - direct link. This explained the doublets observed in the 1H NMR spectra for these compounds, which had puzzled us. This is interesting chemistry-wise, but there is more than just understanding what is going on to control future chemistry: when we look back, other products have these characteristic doublets for the pyrazine protons. The implication is that some N- and S- linked compounds, believed to be inactive, may not be so because the structure is not what we thought - it was an 'Aussie' 8-position compound that was actually tested.

What are we doing about it?

Marat, Ed and myself are each planing to look at some aspect of this in due course.

@maratsydney will be undertaking a systematic study of these reactions, initially by using identical conditions while varying the nucleophile (X = NH2, OH, SH) to see which product is obtained in each case. Control experiments eg. without added nucleophile will also be done, as well as varying the substitution on the core structure.

@edwintse will look at the thiol cases - Ed has previously made thio-linked compounds so will be checking the substitution pattern obtained.

I will attempt to make the 5-nitrogen linked compounds by varying the reaction conditions and/or using a different starting point such as the uncyclised core intermediate for the coupling step.

[MFernflower]

If the 5-amines and 5-sulfides/sulfones are indeed potent (fingers crossed) it will open up a new world of SAR for us to look into!

[MFernflower]

Also I came up with a yet another name for these molecules: "Crazy Eights" @david1597

[mattodd]

Just installing link to #47 and #39 where the central issue of hardness/softness of the nucleophile has already been mentioned. Collation of data needed to establish whether this is the deciding factor. Also to highlight @drc007 's suggestion of resubjecting compounds to reaction conditions to establish whether rearrangements are influenced by factors other than identity of nucleophile.

[maratsydney]

Here is x-ray files for these compounds:

[mcoster]

Cool, thanks for posting those @maratsydney - interesting that 31-2a is almost perfectly orthogonal and 31-2b is co-planar. Would love to see what aryl-substituted compounds look like compared to the pyrazole.

[MedChemProf]

I was wondering if anyone could point me in the direction of the NMR data for an 8-substituted compound? Thanks.

[mattodd]

The reaction code there ought to point you in the direction of the raw NMR data in the ELN. Let's see if it works...

https://au-mynotebook.labarchives.com/share/Marat%2520Korsik/MzUzLjZ8MjkzNzAvMjcyL1RyZWVOb2RlLzE2NjI3NzIzMDJ8ODk3LjU5OTk5OTk5OTk5OTk=

[mattodd]

? I'm getting to the correct ELN page with that link in a browser that's not signed in, and I'm seeing the file there (.mnova file type - someone can advise better than me how best to manipulate that).

[maratsydney]

@MedChemProf please find attached pdf and raw data (processed mnova files and unprocessed files from bruker) for both isomers 5 and 8. Mnova lite used to be included in chemdraw package, not sure about now.

MK113b.pdf
MK113a.pdf
Raw NMR MK113.zip

[MedChemProf]

@mattodd @maratsydney @MFernflower Found what I needed. Thank you!