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17th February 2012 @ 02:55
PS = Pictet-Spengler

START: 17/02/12
FINISH: 12/03/12

Background
The previously performed KAB1-3 experiment was run concurrent with KAB8-11 and the start of KAB8-12. The conditions were analogous to KAB8-11. After 4 hours it was clear the KAB8-11 reaction would not proceed as expected. At this time, the KAB1-3 reaction had been running for 2 hours, with little progress. KAB8-11 was terminated and KAB8-12 immediately started. Within 5 minutes, the reaction was well under way, while the KAB1-3 reaction mixture mostly consisted of starting material. The KAB1-3 reaction was stopped and KAB1-4 started under the same conditions as KAB8-12.

Scheme%20KAB1-4.png
Table%20KAB1-4.jpg

Hazard and Risk Assessment
As for KAB1-3.
Hazard and Risk Assessment KAB1-3


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

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 PZQ analogue (KAB1-6)

Procedure

17/02/12
MNR8-3 (318.8 mg, 0.616 mmol) was dissolved in toluene (35 mL) before the addtion of TfOH (6.08 μL, 0.69 mmol, 10 mol%) at rt. The reaction mixture was immediately placed in a pre-warmed oil bath (90 °C) and reflux heated, with stirring, from 14:10.
Reaction mixture (1 h)

The reaction progress was monitored by TLC against the MNR8-3 starting material and the expected product, identical to KAB1-2.

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).jpg
TLC of reaction mixture (15 min).jpg
TLC of reaction mixture (30 min).jpg
TLC of reaction mixture (1 h).jpg
TLC of reaction mixture (2 h).jpg


After two hours, the reaction vessel was removed from the oil bath and allowed to cool. The orange reaction mixture was diluted with EtOAc (50 mL), transferred to a separating funnel 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 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
Second extraction with EtOAc
Third extraction with EtOAc
Combined organic fractions
Drying combined organic fractions over MgSO4

Filtering through silica

The very pale yellow filtrate was concentrated under reduced pressure to give crude KAB1-4 as a yellow oil. The crude product was stored in the freezer over the weekend to promote crystallisation.
Crude KAB1-4


20/02/12
No crystallisation over the weekend. The KAB1-4 yellow oil was put under high vacuum for 2 hours, after which it became a semi-solid oil (252 mg, 99%). NMR matches that of MNR11-16 (Synthesis of MNR11-16). No further purification required.
Raw H-NMR KAB1-4
Crude KAB1-4

Attempted recrystallisation from EtOAc/hexane and put in the freezer overnight.

21/02/12
No significant crystallisation. The product "oiled" out at the bottom of the flask. The solvent was removed under reduced pressure and the sample put under high vacuum to give an off-white foam.
KAB1-4 foam


22/02/12
Reattempt at the recrystallisation. The foam was dissolved in minimal EtOAc with heating. Hexane (5-7 drops) was added, dropwise, resulting in the brief formation of a white precipitate. The yellow solution was sealed and stored at rt overnight.

27/02/12
Previous recrystallisation failed.

Summary and Conclusion
Successful cyclisation of MNR8-3 catalysed by TfOH (10 mol%). Final isolated yield 99%.



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NOTES 17/02/12
- Used automatic pipette (P20) to add TfOH. Fast transfer seems to be alright, but the TfOH quickly destroys the pipette tip. Recommend using the yellow tip - TfOH is slightly viscous.
- Flask 51.8184 g

NOTES 21/02/12
- Will NMR the foam tomorrow to determine whether or not another attempt at the recrystallisation is necessary.

NOTES 28/02/12
- Some white crystals. Attempted recrystallising old crude KAB1-2 sample to screen reXST conditions.

NOTES 02/03/12
- Will attempt reXST one more time.
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Linked Posts
Attached Files
Scheme KAB1-4
Table KAB1-4
TLC of reaction mixture (5 min).jpg
TLC of reaction mixture (30 min).jpg
TLC of reaction mixture (1 h).jpg
TLC of reaction mixture (2 h).jpg
TLC of reaction mixture (15 min).jpg
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
Combined organic fractions
Drying combined organic fractions over MgSO4
Filtering through silica
Reaction mixture (1 h)
Crude KAB1-4
Crude KAB1-4
KAB1-4 foam
Raw H-NMR KAB1-4