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19th February 2012 @ 23:51
PS = Pictet-Spengler

Conclusion:
Obtained enamide intermediate. Zero conversion to praziquantel product.


START: 20/02/12
FINISH: 02/03/12

Background
Obtaining yield for the TfOH (10 mol%) catalysed Pictet-Spengler reaction series.

Scheme%20KAB3-17.png
Table%20KAB3-17.jpg

Hazard and Risk Assessment
Hazard and Risk Assessment KAB3-17


Previous Related Experiments
TfOH catalysed PS* reaction to give the N-benzoyl PZQ analogue (KAB7-3)
TfOH catalysed PS* reaction to give the dimethoxy PZQ analogue (KAB1-4)
The TfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-12)
TfOH catalysed PS* reaction to give PZQ (KAB3-12 to KAB3-16)

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
KAB5-2 (346.7 mg, 0.857 mmol) was dissolved in toluene (42 mL). TfOH (7.58 μL, 0.086 mmol, 10 mol%) was added at rt at 12:12 and the reaction vessel was immediately placed in a pre-heated oil bath at 90 °C. The reaction progress was monitored by TLC.
Before the addition of TfOH
Just after the addition of TfOH
Reaction mixture (15 min)


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)


After 2 hours, the dark red-brown reaction mixture was removed from heat and allowed to cool. The solution was diluted with EtOAc (50 mL) then quenched with saturated sodium bicarbonate solution (50 mL).
Reaction mixture after removal from heat
After dilution with EtOAc
Quenched with NaHCO3

The organic layer was separated and the aqueous layer extracted with EtOAc (3 × 30 mL). The organic fractions were combined then dried over magnesium sulfate.
First extraction with EtOAc
Second extraction with EtOAc
Third extraction with EtOAc
Left: aqueous fraction; Right: combined organic layers
Drying combined organic fractions over MgSO4

The solution was passed through a silica pad and the filtrate concentrated under reduced pressure to give a dark reddish oil from which a solid began to precipitate out of. The oil was put under a high vacuum and the solvent was rapidly removed to give crude KAB3-17 as a yellowish solid (225.3 mg).
Filtering through silica
KAB3-17 filtrate
Concentrated KAB3-17
Crude KAB3-17


Recrystallisation.
The crude product was recrystallised from EtOAc/hexane and left to stand at rt.
Start mass: 213.9 mg
KAB3-17 crystals

29/02/12
Crystals so far: 63.8 mg, as white crystals. Still some in mother liquor.
The mother liquor was concentrated under reduced pressure and the residue recrystallised from EtOAc/hexane. The off-white crystals were filtered then washed with hexane and dried.

Final yield after recrystallisation: 186 mg, 73%.

Summary and Conclusion
See KAB7-3.

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NOTES 29/02/12
- Filter paper 0.1283 g

NOTES 03/03/12
- Going over HNMR. Suggests presence of starting material and some intermediate. Need to re-record NMR of isolated crystals to double check.
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Linked Posts
Attached Files
Scheme KAB3-17
Hazard and Risk Assessment KAB3-17
TLC of reaction mixture (5 min)
Table KAB3-17
TLC of reaction mixture (15 min)
Before the addition of TfOH
Just after the addition of TfOH
Reaction mixture (15 min)
TLC of reaction mixture (30 min)
TLC of reaction mixture (1 h)
TLC of reaction mixture (2 h)
Reaction mixture after removal from heat
After dilution with EtOAc
Quenched with NaHCO3
First extraction with EtOAc
Second extraction with EtOAc
Third extraction with EtOAc
Left: aqueous fraction; Right: combined organic layers
Drying combined organic fractions over MgSO4
Filtering through silica
KAB3-17 filtrate
Concentrated KAB3-17
Crude KAB3-17
KAB3-17 crystals