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26th January 2012 @ 21:40
*PS = Pictet-Spengler

*****Experiment concluded on 30/01/12.


Background

Scheme%20KAB8-5.png
Table%20KAB8-5.jpg
Table%20KAB8-6.jpg

Hazard and Risk Assessment
Hazard and Risk Assessment


Previous Related Experiments
The silver(I) triflate catalysed PS to give the dimethoxy N-benzoyl PZQ analogue (KAB8-4)
Silver(I) triflate catalysed preparation of the dimethoxy N-benzoyl PZQ enediamide (KAB11-2)
Lewis acid catalysed preparation of the dimethoxy N-benzoyl PZQ enediamide (KAB11-1)

Following Experiments
TfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-7 & KAB8-8)

Procedure

Start: 27/01/12
Finish: 30/01/12

The MNR10-1 starting material was dissolved in toluene before the addition of either triflic acid (TfOH) or silver trifluoroacetate.

KAB8-5.
MNR10-1 - 0.1018 g, 0.222 mmol
Toluene - 34 mL
TfOH - 2 drops, ~20 mg, 60 mol%

KAB8-6.
MNR10 - 97.8 mg
Toluene - 34 mL
AgCO2CF3 - 28.1 mg, 60 mol%

Both mixtures were heated to 90 °C from 10:10. The reaction progress was monitored by TLC. Aliquots (0.1 mL) were extracted and run against the MNR10-1 starting material and the expected product (identical to KAB8-1).

27/01/12
10:40 - Aliquot 1
12:20 - Aliquot 2
15:05 - Aliquot 3
17:20 - Aliquot 4

30/01/12
08:45 - Aliquot 5

Monitoring the Reaction Progress by TLC
All TLCs were eluted with EtOAc/hexane, 4:1, v/v, with a KMnO4 stain.
TLC of reaction mixtures (1)
TLC of KAB8-6 reaction mixture (2)
TLC of reaction mixtures (3)
TLC of reaction mixtures (4)

TLC Legend (Aliquot numbers indicated by the circled number at the bottom of the plate; from L to R): 8-5 - Aliquot of the KAB8-5 reaction mixture; Co - Co-spot of the extracted KAB8-5 aliquot, the MNR10-1 starting material and the expected product; SM - The MNR10-1 starting material; 8-1 - The expected product, identical to KAB8-1; Co - Co-spot of the extracted KAB8-6 aliquot, the starting material and the expected product; 8-6 - The extracted KAB8-6 aliquot.

Work-Up - KAB8-5
27/01/12. The reaction mixture was taken off heat and allowed to cool at 11:00. The pH of the reaction mixture was 5 before it was quenched with saturated sodium bicarbonate solution (50 mL). The organic fraction was set aside and the aqueous layer was extracted withe EtOAc (4 × 30 mL). The organic layers were combined (cloudy, off-white solution) then dried over magnesium sulfate, after which the solution turned clear and colourless. The combined organic layers were then concentrated under reduced pressure to give an off-white/yellowish residue, which was dissolved in EtOAc. The pale yellow solution was passed through a silica pad. The filtrate was collected and concentrated in vacuo to give crude KAB8-5 as an off-white, gummy solid (49 mg, 60 %). The solid was re-crystallised from EtOAc/hexane and stored in the freezer over the weekend.
02/01/12. The white crystals were filtered and washed with hexane to give KAB8-5, the dimethoxy N-benzoyl PZQ analogue as off white crystals (91.3 mg, 112%).
The NMR showed some solvent contamination (hexane and EtOAc).

Work-Up - KAB8-6 - 30/01/12
Final TLC (5) of the reaction mixture, taken 70 hours after heating, suggested the major component was the MNR10-1 starting material. However, there were some unknown spots with Rf unlike the expected product, the enediamide intermediate or the starting material.
No workup was performed and product was taken no further.


Conclusion



TO DO:
- Dry crystals under high vacuum and re-calculate yield.
- Upload NMR
- Write conclusion.


References
Todd, M. H., Ndubaku, C. & Bartlett, P. A., J. Org. Chem. 2002, 67, 3985-3988 - DOI: 10.1021/jo010990m (Paper)


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NOTES 27/01/12
- Estimated TfOH mass by weighing 10 drops then 5 drops: 10 drops = 0.1029 g (10.3 mg/drop); 5 drops = 48.3 mg (9.66 mg/drop).
- A white solid precipitated out, before quickly dissolving, immediately after the addition of TfOH to the MNR10-1/toluene mixture.
- The crude KAB8-5 appeared solid-ish. Attempt to recrystallise from EtOAc/hexane did not work. TLC of the crude product showed impurities, so the product was filtered through a silica pad.

NOTES 28/01/12
- Check reactivity of reaction components.
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Linked Posts
Attached Files
Scheme KAB8-X
Hazard and Risk Assessment
Table KAB8-5
Table KAB8-6
TLC of reaction mixtures (1)
TLC of KAB8-6 reaction mixture (2)
TLC of reaction mixtures (3)
TLC of reaction mixtures (4)