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1st March 2012 @ 21:11
PS = Pictet-Spengler

START: 02/03/12
FINISH:

Background
Analogous reaction to KAB8-15.




Hazard and Risk Assessment
Hazard and Risk Assessment KAB1-6


Previous Related Experiments
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)
TfOH catalysed PS* reaction to give the dimethoxy PZQ analogue (KAB1-4)

Following Experiments
AgOTf catalysed partial PS reaction to give the N-benzoyl PZQ analogue enamide (KAB17-2)

Procedure
02/03/12. Reaction performed under anhydrous conditions. MNR8-3 (404 mg, 870 mmol) was dissolved in anhydrous toluene (40 mL) before the addition of AgOTf (26.0 mg, 101 mmol, 12 mol%). The clear, colourless mixture was immediately placed in a pre-heated oil bath and reflux heated at 90 °C from 09:15.
Reaction mixture (4 h)
Reaction mixture (26 h)


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, MNR8-3 starting material and the expected product, (3)MNR8-3 starting material, (4)Expected product identical to KAB1-2
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)

TLC of reaction mixture (3 h)
TLC of reaction mixture (4 h)
TLC of reaction mixture (5 h)
TLC of reaction mixture (7 h)
TLC of reaction mixture (8 h)

TLC of reaction mixture (26 h)


TLC of the reaction mixture 8 hours after the addition of the AgOTf suggested complete consumption of the MNR8-3 starting materia. The reaction was left to run overnight.

Workup Procedure
03/02/12. TLC of the reaction mixture at 26 hours suggested little change since the last TLC at 8 hours, where most of the mixture was product with some enamide intermediate and polar impurities.
The dark orange-brown reaction was taken off heat at 26 hours and allowed to cool. Reduced silver was visible coating the inside of the flask as a silty metallic film.
Silver residue stuck in the flask

After dilution with EtOAc (50 mL) the mixture was transferred to a separating funnel and washed with citric acid solution (0.5 M, 50 mL). The organic layer was separated and the acidic aqueous layer was adjusted to pH 10 with sodium hydroxide solution (2 M). The basic aqueous solution was extracted with EtOAc (3 × 50 mL). The organic fractions were combined, dried over magnesium sulfate, filtered then concentrated under reduced pressure to give crude KAB1-6 as a brown foam (345 mg, 106%).
TLC of crude KAB1-6


Purification 05/03/12
Silica gel column chromatography, eluting with neat EtOAc.
Start mass: 0.341 mg.
Column of crude KAB1-6
Fractions 23-36
Fractions 35-47

TLCs were eluted with neat EtOAc and stained with KMnO4.
Fractions 23 to 43 were combined then concentrated under reduced pressure to give KAB1-6 as an off white solid (250 mg, 78%).


Summary and Conclusion


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NOTES 02/03/12
- 4 hours. Only starting to see product now. Reaction mixture was momentarily removed from the oil bath under the assumption that the reaction had not proceeded further. On resolution of the TLC taken at 4 hours, which suggested formation of product, the reaction vessel was promptly placed back into the oil bath and shielded from light.
- 8 hours. Only product and enamide intermediate with some polar baseline products. Reaction left overnight to see if reaction proceeds to product with reduction of [enamide].

NOTES 03/03/12
- Flask weight: 60.684 g
- After difficulties attempting to reXST previous dimethoxy PZQ samples, the crude product will be purified by silica gel column chromatography on monday (05/03/12).

NOTES 05/03/12
- Column used was too big.
- Unintentionally scratched silica off the fractions plate when staining. Note to be more careful in future. Not the first time that's happened.
- NMR of product to be recorded as soon as possible.
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Linked Posts
Attached Files
Hazard and Risk Assessment KAB1-6
Scheme KAB1-6
Table KAB1-6
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 (3 h)
TLC of reaction mixture (2 h)
TLC of reaction mixture (4 h)
TLC of reaction mixture (5 h)
TLC of reaction mixture (7 h)
TLC of reaction mixture (8 h)
Reaction mixture (4 h)
TLC of reaction mixture (26 h)
Reaction mixture (26 h)
Silver residue stuck in the flask
TLC of crude KAB1-6
Fractions 23-36
Fractions 35-47
Column of crude KAB1-6