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30th January 2012 @ 04:54
*PS = Pictet-Spengler

TO DO:
- Write conclusion

START: 30/01/12
FINISH: 02/02/12

Background
Further reduction of catalyst loading. See procedure for the preparation of KAB8-7 and KAB8-8.

Scheme%20KAB8-9.png


Hazard and Risk Assessment
As for KAB8-5 (here)

Previous Related Experiments
TfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-7 & KAB8-8)
Controls for the AgOTf catalysed PS* to give the dimethoxy N-benzoyl PZQ analogue (KAB8-5 & KAB8-6)
The silver(I) triflate catalysed PS to give the dimethoxy N-benzoyl PZQ analogue (KAB8-4)

Following Experiments
The TfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-11)
The TfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-12)
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
MNR10-1 (123.8 mg, 0.270 mmol) was dissolved in toluene (33 mL) before the addition of TfOH/toluene* (51.9 uL, 0.25 M, 13.5 umol) at rt. The clear, colourless reaction mixture was reflux heated at 90 °C from 15:35.
Reaction mixture at 1 hr

The reaction progress was monitored by TLC of extracted aliquots (20-50 uL) against the MNR10-1 starting material and the expected product (identical to KAB8-1). The TLCs were eluted with EtOAc/hexane, 4:1, v/v and stained with KMnO4.

30/01/12
15:40 - Aliquot 1
16:00 - Aliquot 2
16:15 - Aliquot 3
16:30 - Aliquot 4
16:45 - Aliquot 5
17:15 - Aliquot 6
18:00 - Aliquot 7

31/01/12
08:45 - Aliquot 8
09:00 - Taken off heat

TLC of reaction mixture (1)
TLC of reaction mixture (2)
TLC of reaction mixture (3)
TLC of reaction mixture (4)


31/01/12. TLC of the extracted aliquot 8 suggested no change had occurred overnight and the reaction mixture contained the enediamide intermediate, in lower concentration, and the major component, the completely cyclised product (identical to KAB8-1).
The reaction mixture was quenched after 22 hours, with saturated sodium bicarbonate solution (50 mL). The organic fraction was separated and the aqueous layer extracted with EtOAc (3 × 30 mL). The organic layers were combined, dried over magnesium sulfate, filtered, then concentrated under reduced pressure to give crude KAB8-9 as a pale yellow oil. The product began crystallising on standing and was put in the freezer overnight to promote crystallisation.
Crystals forming


02/01/12
The crystals were filtered and washed with hexane to give KAB8-9 as pale orange crystals (92.4 mg, 93%). 1H-NMR confirmed KAB8-9 as the dimethoxy N-benzoyl PZQ analogue.
H-NMR KAB8-9
Raw H-NMR KAB8-9



Summary and Conclusion


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NOTES 30/01/12
- TfOH/toluene solution made up in previous experiment (here).
- First time seeing a decent amount of the enediamide intermediate with the TfOH reaction. The unknown low Rf spot started to disappear just as the high enediamide spot appeared.
- 17:24. The enediamide spot hasn't got less intense over the last 30 minutes. Will leave the reaction overnight. The amount of acid may be low enough that if it the reaction goes to completion overnight, the product won't decompose (too much).

NOTES 31/01/12
- Still no apparent change based on TLC. i.e. reaction contains intermediate and product.
- After work-up: product stored in freezer.
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Linked Posts
Attached Files
Scheme KAB8-9
TLC of reaction mixture (1)
TLC of reaction mixture (2)
Reaction mixture at 1 hr
TLC of reaction mixture (3)
TLC of reaction mixture (4)
TLC of reaction mixture (4)
Crystals forming
H-NMR KAB8-9
Raw H-NMR KAB8-9