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Pictet-Spengler route to Praziquantel
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15th February 2012 @ 22:54
PS = Pictet-Spengler

START: 16/02/12
FINISH: 17/02/12

Background
Repeat of KAB8-9. Aim of experiment was to determine ideal conditions for the TfOH catalysed PS to give all three PZQ analogues - obtain yield for the different substrates under analogous conditions.

Scheme%20KAB8-11.png
***MNR10-1 should read MNR10-2
Table%20KAB8-11.jpg

Hazard and Risk Assessment
Hazard and Risk Assessment KAB8-11


Previous Related Experiments
TfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-9)
Preparation of the dimethoxy Ugi-intermediate (MNR10-2 and MNR10-3)

Following Experiments
The TfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-12)
TfOH catalysed PS* reaction to give the dimethoxy PZQ analogue (KAB1-3)
TfOH catalysed PS* reaction to give the dimethoxy PZQ analogue (KAB1-4)
TfOH catalysed PS* reactions to give the dimethoxy PZQ analogues (KAB8-14 & KAB1-5)
AgOTf catalysed PS reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-15)

Procedure
16/02/12 - MNR10-2 (278.9 mg, 0.608 mmol) was dissolved in dried toluene (30 mL). Microwave activated 4 A molecular sieves were added. The mixture was put in the freezer overnight.
17/02/12 - The reaction mixture was removed from the freezer and allowed to warm to rt. TfOH (74.6 mg, 0.497 mmol) was added to a volumetric flask (25 mL). The volume made up with dried toluene to give the TfOH/toluene stock acid solution (19.9 mM).
The reaction mixture was cooled in an ice bath before the addition of the stock acid solution (1.5 mL, 0.030 mmol, 5 mol%) at 9:55. The reaction mixture was reflux heated to 90 °C and the reaction progress monitored by TLC against the MNR10-2 starting material and the expected product identical to KAB8-4.
Reaction Setup


TLC of the reaction mixture after 4 hours suggested most of the reaction mixture consisted of starting material, with some unknown intermediate with low Rf. The reaction was terminated at 13:00. The solution was removed from heat and allowed to cool. No workup was performed and the following experiment - KAB8-12 was started immediately.

Monitoring the Reaction Progress by TLC
All TLCs were eluted with EtOAc/hexane, 5:3, v/v and stained with KMnO4. The time noted is from the addition of the acid.
TLC of reaction mixture (5 min)
TLC of reaction mixture (15 min)
TLC of reaction mixture (30 min)
TLC of reaction mixture (1 h)
TLC of reaction mixture (2 h)

TLC of reaction mixture (3 h)
TLC of reaction mixture (4 h)


Summary and Conclusion
The reaction did not proceed as expected based on the previous experiment under identical catalyst load (KAB8-9). At first, it was thought the cause of the apparently slowed reaction was a result of storage of the substrate mixture (MNR10-2/toluene/MS) in the freezer overnight. Two alternative suggestions for the lack of reaction were the presence of the 4 A MS and possibly some reaction of the TfOH with toluene, from the preparation of the stock acid solution.
However, it was more likely the presence of MS in the reaction mixture was was the cause of failures no TfOH-toluene reactivity was observed in previous experiments involving the preparation of TfOH/toluene stock solutions (KAB3-12 to KAB3-16, KAB8-7 to KAB8-9).


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NOTES 16/02/12
- Made a mistake (added too much TfOH to the stock acid solution). Not enough time to start and finish the reaction (reaction + workup 5-7 hours). The made up toluene-MNR10-2 reaction mixture was sealed and put in the freezer overnight. Will start first thing in the morning.

NOTES 17/02/12
- Expecting product to appear at least 3.5 hours into the reflux.
- Terminated reaction. Product should have appeared by now, something's not right. Attempting re-start KAB8-12.
- No colour! See KAB8-12. Turned yellow <10 min.

NOTES 18/02/12
- Mol sieve - fit TfOH? if not it definitely fits EtOH (leaving group). Is the reaction autocatalytic?? Still observed formation of the low spot reaction intermediate. But none of the other intermediates observed previously.
- If TfOH fits - acid gets consumed.

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Linked Posts
Attached Files
Scheme KAB8-11
Hazard and Risk Assessment KAB8-11
Hazard and Risk Assessment KAB8-11
Table KAB8-11
TLC of reaction mixture (5 min)
TLC of reaction mixture (15 min)
TLC of reaction mixture (30 min)
TLC of reaction mixture (1 h)
TLC of reaction mixture (2 h)
TLC of reaction mixture (3 h)
Reaction Setup
TLC of reaction mixture (4 h)
Comments
Re: The TfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-11) by Murray Robertson
16th February 2012 @ 01:46
Hazard and Risk Assessment Approved - MNR