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3rd March 2012 @ 03:48
PS = Pictet-Spengler

START: 05/03/12
FINISH:

Background
Analogous reaction to KAB8-15 and KAB1-6 (see linked posts below).

Scheme%20KAB17-2.png
Table%20KAB17-2.png

Hazard and Risk Assessment
Hazard and Risk Assessment KAB17-2


Previous Related Experiments
AgOTf catalysed PS reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-15)
AgOTf catalysed PS reaction to give the dimethoxy PZQ analogue (KAB1-6)
TfOH catalysed partial PS* reactions to give the enediamide intermediates of PZQ and the N-benzoyl analogue (KAB13-2 & KAB17-1)
TfOH catalysed PS* reaction to give the N-benzoyl PZQ analogue (KAB7-3)

Following Experiments


Procedure
All glassware was oven dried prior to use. The toluene was dried using 4A mol. sieves, then degassed.

05/03/12. KAB6-1 (335 mg, 0.841 mmol) was dissolved in toluene (33 mL) before the addition of AgOTf (24.0 mg, 0.093 mmol, 11 mol%). The mixture was immediately placed in a preheated oil bath and reflux heated at 90 °C, shielded from light at 12:25.

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 AgOTf. TLC Legend (from L to R): (1)Reaction mixture at time indicated at the bottom, (2)Co-spot of reaction mixture, KAB6-1 starting material and the expected product, (3)KAB6-1 starting material, (4)Expected product identical to KAB17-1, (5)Completely cyclised product
TLC of reaction mixture (5 min)
TLC of reaction mixture (15 min)
TLC of reaction mixture (1 h)
TLC of reaction mixture (2 h)
TLC of reaction mixture (3 h)


Workup Procedure
After 4 hours the reaction mixture was removed from the oil bath and allowed to cool then diluted with EtOAc (50 mL). The mixture was washed with citric acid solution (0.5 M, 50 mL), the organic layer separated and the acidic aqueous layer made alkaline with NaOH (2 M).
Reaction mixture after removal from heat
Washed with citric acid solution
Acidic aqueous fraction
Aqueous fraction after basification

The aqueous layer was then extracted with EtOAc (3 × 50 mL). The organic layers were combined, dried over magnesium sulfate, filtered then concentrated under reduced pressure to give crude KAB17-2 as a dark brown oil (330 mg, 128%).

Purification
The crude product was filtered through a short silica column, eluting with EtOAc. The collected filtrate was concentrated under reduced pressure to give a brown gel (258 mg, 100%).
Raw H-NMR KAB17-2
H-NMR KAB17-2


Summary and Conclusion


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NOTES 07/03/12
- NMR of the filtered product was mostly clean. Still some greasy impurities. Will wash product with Et2O.
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Linked Posts
Attached Files
Scheme KAB17-2
Hazard and Risk Assessment KAB17-2
TLC of reaction mixture (5 min)
TLC of reaction mixture (15 min)
TLC of reaction mixture (1 h)
TLC of reaction mixture (2 h)
TLC of reaction mixture (3 h)
Table KAB17-2
Reaction mixture after removal from heat
Washed with citric acid solution
Acidic aqueous fraction
Aqueous fraction after basification
Crude KAB17-2
Raw H-NMR KAB17-2
H-NMR KAB17-2