Synthesis of 5-(phenethylthio)-3-(4-(difluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine and its oxidised derivatives

[edwintse]

This compound is being synthesised as part of the Series 4 Triazolopyrazine Hypotheticals (see Issue #358). This compound (and the corresponding sulfur oxidations) is a comparison to the analogous compounds synthesised in #377, #376 and #375.

ELN entries: here

Thioether FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(SCCC4=CC=CC=C4)N32 InChI=1S/C20H16F2N4OS/c21-20(22)27-16-8-6-15(7-9-16)19-25-24-17-12-23-13-18(26(17)19)28-11-10-14-4-2-1-3-5-14/h1-9,12-13,20H,10-11H2 GFJJCWGNCVLFNL-UHFFFAOYSA-N

Sulfoxide O=S(CCC1=CC=CC=C1)C2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32 InChI=1S/C20H16F2N4O2S/c21-20(22)28-16-8-6-15(7-9-16)19-25-24-17-12-23-13-18(26(17)19)29(27)11-10-14-4-2-1-3-5-14/h1-9,12-13,20H,10-11H2 XRLPEWWQEWQISU-UHFFFAOYSA-N

Sulfone O=S(C1=CN=CC2=NN=C(C3=CC=C(OC(F)F)C=C3)N21)(CCC4=CC=CC=C4)=O InChI=1S/C20H16F2N4O3S/c21-20(22)29-16-8-6-15(7-9-16)19-25-24-17-12-23-13-18(26(17)19)30(27,28)11-10-14-4-2-1-3-5-14/h1-9,12-13,20H,10-11H2 VHMNWOXAYNBRAI-UHFFFAOYSA-N

[MFernflower]

How difficult would this be to turn into a sulfonamide? If it's easy enough it would be quite a unique linker!

[edwintse]

It seems fairly straightforward to reduce the azide to the amine then couple to a sulfonyl chloride. Might give that a go.

[edwintse]

Going from the starting material of the reversed triazole that is.

[MFernflower]

Do you have any of that left? if you need to make more could you perhaps attempt to replace the phenyl on the linker end with a pyridine? (This appears to give a massive increase in water solubility - at least in silico)

[edwintse]

Yes, I've got some of the azide to spare. It would definitely be good to try to replace the benzene with a pyridine. I've just been going for benzene at the moment as that's what we've had at hand.

[MFernflower]

Sounds great!

[MFernflower]

@edwintse Looks like a sulfonamide linker with a methyl spacer was tested with poor results back in 2014:

However I feel this is poor potency is due to either the use of a nitrogen atom to link to the TP core (A reversed sulfonamide seems like a wise thing to test in the longrun) or because of the greasy CF3 and/or the methyl spacer betwixt the sulfur atom and the phenyl ring - If you still have any of the azide/amine left would you be willing to try and couple it to benzenesulfonyl chloride?

[edwintse]

Ah, I see. I'll give the benzenesulfonyl chloride coupling a go first then.

[MFernflower]

Sounds good!

[edwintse]

The procedure i've found generates the sulfonyl chloride from the thiol in situ, followed by addition of the amine. We've got a couple of aryl thiols that we could try.

[MFernflower]

Two birds with one stone - sounds like a solid plan - Do you have a link to that procedure? I'm a bit curious as to how it works

[edwintse]

10.1021/jo901924m

[MFernflower]

@edwintse Hello again! I was just reading your ELN and saw you produced the left hand cubane - I'm a bit curious as to what the 3-cubylpropanol looked like and what the final product yield was - I love reading your synthesis notes and am wondering when you will start work on the sulfonamides and the right hand cubane!

[edwintse]

@MFernflower Hi, it's great to hear that my notes make sense! I took a quick NMR of the 3-cubylpropanol before I used it so I'll be able to upload that at some point. I've yet to purify it but that should be done on Monday. As for the sulfonamides and the RH cubane - I need to finish up the homologous sulfur series first (I have 2/3 and should have the 3rd also by Monday)

[MFernflower]

@edwintse If you have the time - perhaps we could chat over hangouts?

[edwintse]

@MFernflower sure

[MFernflower]

What is your google+ name so i can add you?

[edwintse]

Edwin Tse

[edwintse]

The target compound was successfully synthesised in 23% yield (314 mg). The corresponding sulfone was successfully synthesised in 65% yield (179 mg). The corresponding sulfoxide was synthesised in 88% yield (262 mg).