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Pictet-Spengler route to Praziquantel
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12th January 2012 @ 22:05
*********Experiment concluded on 13/01/12.

Background
For all Pictet-Spengler reactions performed so far, there has been significant formation of a dark red-brown, highly viscous substance, which was non-miscible with the reaction mixture.

See:
Stoichiometric acid-mediated Pictet-Spengler of MW29-4 to give racemic PZQ (KAB3-1 and KAB3-2)
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)
Acid-mediated Pictet-Spengler reaction to give PZQ (KAB3-4) and the N-benzoyl PZQ analogue (KAB7-2)
Acid-mediated Pictet-Spengler reaction to give PZQ (KAB3-5)
Reattempt acid-mediated Pictet-Spengler reaction to give PZQ (KAB3-6)
Reducing decomposition in the acid mediated Pictet-Spengler to give PZQ (KAB3-7).

During the KAB3-8 attempt at the PS reaction to give PZQ, the non-miscible red substance did not form. The reaction conditions for KAB3-8 were in neat MSA. This experiment was to determine if the solvent used for all KAB3 experiments previously, toluene, was interfering with the reaction by reacting with MSA.

Scheme
Scheme%20KAB9-1%20(amended).png

Hazard and Risk Assessment
KAB9-1 Hazard and Risk Assessment


Procedure
Methanesulfonic acid (1 mL, 15.4 mmol) was added to toluene (5 mL, 46.9 mmol, 3 eq.) and the mixture was left to stir at room temperature.

MSA (left) and Toluene (right) before mixing
Reaction mixture < 30 s after the addition of MSA
Reaction mixture < 10 m after the addition of MSA


Immediately after the addition of MSA, the reaction mixture went cloudy. In less than 5 minutes, it started turning slightly red and there are clearly two phases in the reaction vessel.

After 1.5 hours two aliquots were taken, one of the top phase and one of the bottom phase. Both were diluted in toluene (3 mL) and the pH determined (pH 5). The indicator strips had dried to a lower pH. The photograph shows the "dried indicator strips" on the left and the still wet stick on the right.

pH of the extracted aliquots
Extracted aliquots



After 2 hours, the reaction mixture was diluted with EtOAc (10 mL), then quenched with saturated NaHCO3 (15 mL). Heat and gas were produced on quenching. The organic EtOAc fraction was removed and the aqueous layer further extracted with EtOAc (10 mL).

Reaction after dilution with EtOAc
First extraction with EtOAc


The EtOAc layers were combined then dried over magnesium sulfate. The aqueous fraction had a pH of 8. The combined organic fractions were then filtered and concentrated to give crude KAB9-1 as yellow oil/soild (2 mg).

Conclusions
Not much product to do further analysis on. The toluene is doing something with the MSA. The two phase solution went to a single phase on dilution with EtOAc. If no references are found in SciFinder, I may attempt this experiment again.

Future considerations:
- TLC each phase during the reaction.
- Do not dilute with EtOAc.

Regarding PS cyclisation:
May need to change solvent for future attempts at mediated/catalytic Pictet-Spengler using MSA.


Experiment Concluded.

-----------------------------------------------------------------
- Could explain why the reaction so far has not been catalytic.
- Could also the lack of gas released when quenching previously performed PS reactions (KAB3-5 to KAB3-7).
- Possibly the origin of the dark red colour.
Linked Posts
Attached Files
KAB9-1 Hazard and Risk Assessment
Scheme KAB9-1
MSA (left) and Toluene (right) before mixing
Reaction mixture < 30 s after the addition of MSA
Reaction mixture < 10 m after the addition of MSA
Scheme KAB9-1 (amended)
pH of the extracted aliquots
Extracted aliquots
First extraction with EtOAc
Reaction after dilution with EtOAc