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Alicia's Masters Thesis
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Ugi NMR Analysis
Synthesis of DOPAL
is a key intermediate in the
Ugi synthesis of many of the diketopiperazine anti-malarial targets
we are synthesizing. Since we have not found a commercial source, we have been trying to make it by treating adrenaline with acid, based on a convenient but low yielding one-step decomposition of adrenaline in
85% phosphoric acid
The following are successful experiments to make DOPAL:
(2006-08-31) Khalid/Lin (pure without chromatography)
The story of the failures that made the success possible:
Our initial attempts focused on modifying a
of the decomposition of adrenaline in glacial acetic/perchloric acids in order to avoid using perchloric acid. With limited access to NMR for a few months, we attempted to monitor the progress of the reaction mainly by TLC. Based on
of DOPAL using 20% chloroform in hexanes on silica gel, we assumed that it was soluble in methylene chloride. Unfortunately adrenaline free base is not that soluble in chlorinated solvents, making monitoring its disappearance by TLC very difficult. We interpreted the lack of formation of a UV-active spot in a methylene chloride or benzene extract of the acidic solution as an indication that the aldehyde did not form. In fact, DOPAL
required 2% methanol in methylene chloride
to purify on silica and didn't move in pure methylene chloride.
The turning point came when we discovered that
DOPAL could be extracted into ether
. We did in fact extract a product but the NMR of the aromatic protons did not match
that reported previously
. Details of the NMR data are reported in the discussion section of
. Eventually, we found
another report of the NMR of DOPAL
that matched ours.
Keeping in mind the faulty models we used and incomplete available information, the following are the prior experiments attempting to synthesize DOPAL in our lab. These are either failed or inconclusive (due to NMR problems) attempts.
(5.8 mM), sulfuric acid (0.2 M) in 4:1 methanol/water refluxed for 2h in air did not generate DOPAL, based on the absence of a faster moving spot in TLC.
(5.2mM), glacial acetic acid, 1M sulfuric acid refluxed for 2hr under nitrogen did not generate DOPAL based on the absence of no M+ peak for the catechol aldehyde by FAB.
. Benzene, glacial acetic acid, 6M sulfuric acid
(11.06mM) are stirred and refluxed under nitrogen for 2.5hrs. The video after 60 minutes shows that a small brown layer separates at the bottom of the flask, suggesting that it contains only the aqueous sulfuric acid dissolving the adrenaline.
(9.43mM), 6M sulfuric acid and benzene, was refluxed for 24 hours under nitrogen. Because the benzene layer was not UV active when spotted, it seems that no significant amount of
(20.78mM) with concentrated sulfuric acid, benzene and water was refluxed for 24 hours under nitrogen. If the aldehyde formed in the benzene layer, which the slight movement on the TLC plate would suggest, in this
shot ,then the reaction is working. However the concentration is low and the movement can not be seen well. Any amines, including the
starting material, should remain in the acidic aqueous phase. The TLC plates were stained with Ninhydrin and it shows that there are no amines in the benzene layer.
(21.46mM) with concentrated sulfuric acid and a benzene layer was refluxed 24 hours under nitrogen. We would expect the
to partition in the organic phase of a benzene/aqueous sulfuric acid mixture and be UV active when spotted on a TLC plate, but did not observe this even after 24 hours of reflux.
(15.48mM) with concentrated sulfuric acid was held at 70C for 24 hours under nitrogen. TLC of methylenechloride and benzene extracts revealed no spot.
(26.66mM) was added to a 100mL round bottom flask with glacial acetic acid and water was refluxed 24 hours under nitrogen. TLC results of what
remained from vacuum pump
show some movement in
1:1 methylene chloride methanol
Also in pure methanol
(1.18mM) in 85% phosphoric acid (6 mL) was heated in a 12mL vial to 120C in a glycerol bath then removed from heat and allowed to cool for 30 secondsthen added to water (36 mL) and then saturated with NaCl, followed by extraction with ether
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