MedChemProf
commented
6 years ago @edwintse I would tend to agree with the notion that all you are seeing is an artifact of concentration in the NMR in regards to the hydrazinyl intermediates. Unlikely, but do you happen to have any of their samples still available? If so, I would just mix the two and you would probably see a uniform spectra. A D2O washed sample might be worth running for comparison to future samples if your resynthesis does not go according to plan. In regards to the unknowns created by the students, you did not mention if they performed any LCMS runs on their products. From the complexity of the NMR, I would hazard a guess that the products might be heavy by the weight of a second pyrazine (or portion of the triazolopyrazine) due to some self-condensation while sitting unpurified throughout their synthesis.
edwintse
mattodd
MFernflower
Alternative Oxidative Cyclization:
bendndi
david1597
drc007
holeung
For the past 4 years, the first year Special Studies Program here at the University of Sydney have been synthesising new Series 4 compounds. This year, their target compounds were based around modification of the RHS aryl group with non-aromatic heterocycles (highlighted in green).
The synthesis plan followed the typical route. The initial hydrazine SM was provided to them by us. This was then condensed with a commercially available CHO, cyclised and finally coupled with 2-phenylethanol.
Upon completion of the synthesis in the undergrad labs, I made attempts at purifying their crude products. This is where things became problematic... I ran the 4 compounds through 3 Isolera columns each (1 regular, 2 reverse phase), however none of the compounds ended up clean. Either the aliphatic region was still broad and messy or the aromatic region still had multiple impurity peaks, both of which I would have expected reverse phase to have cleaned up. I suspect that this may have been due to the a couple of reasons: Reactions could only be performed once a week within the timeframe of the 3 h lab. Reactions were left sitting until the next weeks lab session. Crude material was taken through for each step from the beginning.
Good news ––––––––––––––– I ended up resynthesising the 4 compounds with purifications of each intermediate before subsequent steps. The two protected amines were also deprotected to give a total of 6 compounds that will be sent for evaluation tomorrow. My ELN entries are here.
Not so good news ––––––––––––––– A comparison of their final products and the ones that I made are not consistent. In the spectra below, their compounds (after the 3 columns) are on top in blue and mine are below in red. It is clear that there are a number of differences between the spectra.
It is evident from this that they seem to have actually not made the desired compounds but something different.
The only characterisation that the students performed was a 1H NMR of their crude condensation products. Comparison of these NMRs has identified yet another inconsistency. Again, their compounds are on top in blue and mine are below in red.
The only explanation for this is that they've somehow made the other isomer of the condensation product. The only difference between the reaction conditions is that they used E95 ethanol and I used E100 ethanol but I'm not sure how this would have made such a difference. No recrystallisations were done in either case. This may have also have influenced them not making the final products, however, I'm again not sure how this would have affected the subsequent cyclisation?
I will look into the possibility that this could be due concentration dependence of the NMR samples to see if there's any shift in that signal. I will also get LRMS of their compounds to see if it matches.