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17th February 2012 @ 02:17
PS = Pictet-Spengler

****Experiment Concluded.

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Summary and Conclusion
The lower loading of triflic acid in the catalytic Pictet-Spengler reaction to give the dimethoxy N-benzoyl PZQ analogue was fast and efficient (yield 92%).
The yield for the reaction could potentially have been slightly higher, as the recrystallisation was terminated prematurely, with some product remaining in the filtrate. Further attempts to isolate the remaining product were unsuccessful. Recommend performing TLC of the recrystallisation mother liquor before filtering out the formed crystals.
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START: 17/02/12
FINISH: 27/02/12

Background

Scheme%20KAB8-12.png
Table%20KAB8-12.jpg

Hazard and Risk Assessment
As for KAB8-11
Hazard and Risk Assessment KAB8-11


Previous Related Experiments
The TfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-11)
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
TfOH catalysed PS* reactions to give the dimethoxy PZQ analogues (KAB8-14 & KAB1-5)
TfOH catalysed partial PS* reactions to give the enediamide intermediates of PZQ and the N-benzoyl analogue (KAB13-2 & KAB17-1)
AgOTf catalysed PS reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-15)

Procedure

17/02/12

MNR10-2 (337.2 mg, 0.735 mmol) was dissolved in toluene (35 mL). TfOH (6.48 μL, ~0.074 mmol, 10 mol%) was added at rt before the reaction mixture was immediately placed in a pre-heated oil bath at 90 °C. The mixture was reflux heated from 13:13.
Reaction mixture (<10 min)
Reaction mixture (1 h)


Monitoring the Reaction Progress by TLC
All TLCs were eluted with EtOAc/hexane, 5:3, v/v and stained with KMnO4. Time noted is the amount elapsed since the addition of 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 (1.5 h)

TLC of reaction mixture (2 h)


TLC of the reaction mixture after 2 hours suggested no significant consumption of the enediamide intermediate. The reaction vessel was removed from the oil bath and allowed to cool. After dilution with EtOAc (50 mL), the reaction mixture was transferred to a separating funnel then quenched with saturated sodium bicarbonate solution (50 mL).
After dilution with EtOAc
Quenched with NaHCO3

The organic layer was separated and the aqueous layer further extracted with EtOAc (3 × 30 mL). The organic fractions were combined and the cloudy orange-brown solution dried over magnesium sulfate to give a clear orangish solution, which was then passed through a silica pad.
First extraction with EtOAc
Third extraction with EtOAc
Drying combined EtOAc fractions over MgSO4
Filtering through silica

The very pale yellow filtrate was concentrated under reduced pressure to give crude KAB8-12 as a yellow, semi-solid oil (295 mg, 109%), which was stored in the freezer over the weekend.
Crude KAB8-12


20/02/12
Solid/crystals had formed over the weekend.
Crude KAB8-12


Purifcation
The product was recrystallised from EtOAc/hexane, 1:1, v/v, and put in the freezer overnight. Started to see formation of white crystals.

21/02/12
The crystals were filtered then washed with hexane. TLC of the filtrate and the isolated crystals against the expected product (identical to KAB8-4) suggested the filtrate still contained a mixture of the enediamide intermediate and the final product. The filtrate was concentrated under reduced pressure.
Repeated recrystallisation from EtOAc/hexane.
Yield so far: (247 mg, 92%).
KAB8-12 crystals
Filtered and washed crystals
TLC of crystals and filtrate


27/02/12
Orange crystals (45.6 mg) were obtained from the repeated re-crystallisation. TLC of the crystals indicated that they were a mixture of the enediamide intermediate and the expected product. TLC of the filtrate showed no spots.
No further purification of the product was performed.

Characterisation
H-NMR KAB8-12
Raw H-NMR KAB8-12

m.p. 119 °C - 12X °C.

Summary and Conclusion
The lower loading of triflic acid in the catalytic Pictet-Spengler reaction to give the dimethoxy N-benzoyl PZQ analogue was fast and efficient (yield 92%).
The yield for the reaction could potentially have been slightly higher, as the recrystallisation was terminated prematurely, with some product remaining in the filtrate. Further attempts to isolate the remaining product were unsuccessful. Recommend performing TLC of the recrystallisation mother liquor before filtering out the formed crystals.

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NOTES 17/02/12
- Flask weight: 54.2623 g

NOTES 21/02/12
- Filter paper: 1.1261 g

NOTES 27/02/12
- Filter paper: 1.1105 g
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Linked Posts
Attached Files
Scheme KAB8-12
Table KAB8-12
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 (1.5 h)
Reaction mixture (<10 min)
TLC of reaction mixture (2 h)
Reaction mixture (1 h)
After dilution with EtOAc
Quenched with NaHCO3
First extraction with EtOAc
Third extraction with EtOAc
Drying combined EtOAc fractions over MgSO4
Filtering through silica
Crude KAB8-12
Crude KAB8-12
KAB8-12 crystals
Filtered and washed crystals
TLC of crystals and filtrate
H-NMR KAB8-12
Raw H-NMR KAB8-12