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12th January 2012 @ 21:16
***Experiment concluded.

Attempts to reproduce literature results.[1]

Scheme



Hazard and Risk Assessment
As for KAB3-3(here).

Following Experiments


Pre-procedure
Unsure whether the starting material (KAB5-1) had decomposed since its synthesis (see co-spotting in previous experiment KAB3-7). After re-running the TLC and comparison of the re-recorded H-NMR to the originally recorded, it was determined that there was contamination of the solution used in the TLC analysis, and there was no decomposition of the compound.

Procedure

The peptide acetal KAB5-1 (258 mg) was added portionwise to methanesulfonic acid (MSA, 3 mL, 70 eq.) at 0 C, before the reaction mixture was refluxed at 70 C for 6 hours.

Reached 70 C at 08:48

After refluxing for almost 30 minutes, the reaction still appeared relatively "clear" i.e. no formation of the red product typically observed when performing the reaction with 1:1 stoichometry in toluene. A test with a small amount of toluene and MSA was performed. The solution went immediately cloudy and steadily started turning red. The following experiment was performed shortly thereafter: Observation of toluene-methanesulfonic acid mixture (KAB9-1)

At 4 hours, a 10 uL aliquot was extracted from the reaction mixture and diluted with 1 mL of EtOAc. TLC of the aliquot against PZQ (EtOAc/hexane, 3:1, v/v) indicated formation of the expected product PZQ. There was no spot present corresponding to the enediamide tautomerised intermediate.

TLC of the reaction mixture at 4 h


The reaction mixture was removed from heat after 5 hours after reaching 70 C, and allowed to cool. The mixture was poured over an ice-water slurry and the pH adjusted to 8 with NaOH solution (20 %). The aqueous mixture was extracted with diethyl ether (4 x 100 mL). The ether layers were combined, washed with saturated NaCl solution (100 mL), then dried over magnesium sulfate. The solution was filtered then concentrated to give crude PZQ as a yellowish solid (139.3 mg, 70%).

Reaction mixture after removal from heat
Second extraction with ether
Crude KAB3-8


H-NMR of the crude sample was recorded (in CDCl3).
H-NMR of Crude KAB3-8
H-NMR Crude KAB3-8


16/01/12
Recrystallising from EtOAc/hexane, 1:1, v/v. Yield (~65 %)

Conclusion
The experiment outcomes, including yield, were almost exactly as described in the literature.

References
[1] H. Cao, H. Liu, A. Doemling, Chemistry-a European Journal 2010, 16, 12296. DOI: 10.1002/chem.201002046 (Link)


Related Experiments
Preparation of the PZQ analogue Ugi-intermediate (KAB5-1)
Reattempt acid-mediated Pictet-Spengler reaction to give PZQ (KAB3-6)
Acid-mediated Pictet-Spengler reaction to give PZQ (KAB3-5)
Acid-mediated Pictet-Spengler reaction to give PZQ (KAB3-4) and the N-benzoyl PZQ analogue (KAB7-2)
Acid-mediated PS cyclisation to give racemic PZQ (KAB3-3), the dimethoxy N-benzoyl PZQ analogue (KAB8-1), the dimethoxy PZQ analogue (KAB1-2) and the N-benzoyl PZQ analogue (KAB7-1)
Stoichiometric acid-mediated Pictet-Spengler of MW29-4 to give racemic PZQ (KAB3-1 and KAB3-2)
Acid-mediated Pictet-Spengler of MW29 to give rac-PZQ MNR13-1


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NOTES 13/01/12
08:56 It was difficult to add the starting material KAB5-1 "portionwise" as it is a viscous liquid, about the same colour and consistency of honey. I was attempting to add KAB5-1 so there would be about 20 equivalents of MSA to KAB5-1 in the reaction vessel. I estimated badly, so the reaction was started with 70 equivalents of MSA. This probably means the reaction will be over in less than 6 hours. Not sure at this stage whether to let it go for the whole time, or to cut it short.
09:15 MSA REACTS WITH TOLUENE!! Textbook SNAr. Or not. Electrophilic, but no EWGs?
Linked Posts
Attached Files
Scheme KAB3-8
Table KAB3-8
TLC of the reaction mixture at 4 h
Reaction mixture after removal from heat
Second extraction with ether
Crude KAB3-8
H-NMR Crude KAB3-8
H-NMR of Crude KAB3-8