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29th January 2012 @ 23:46
*PS = Pictet-Spengler

Background
Repeat of procedure for the preparation of KAB8-5 with reduced catalyst loading.

Scheme%20KAB8-7.pngTfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-9)



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

Previous Related Experiments
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
TfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-9)

Procedure

Preparation of stock acid: A 0.26 M solution of TfOH in toluene was prepared by mixing TfOH (~195 mg, 1.3 mmol) in toluene (5 mL). It was assumed the TfOH contributed negligible volume.

KAB8-7: MNR10-1 (153.9 mg, 0.336 mmol) was dissolved in toluene (32 mL) before the TfOH/toluene mixture (0.39 mL; TfOH = 30 mol%) was added at 12:30 at rt. The mixture was heated to 90 °C.

KAB8-8: The procedure was the same as for KAB8-7. MNR10-1 (94.8 mg, 0.207 mmol), toluene (32 mL), TfOH/toluene (0.12 mL; TfOH = 15 mol%). Added at 12:35 at rt, before heated to 90 °C.

Aliquot 1 (50 uL) extracted from both solutions at 12:40
Aliquot 2 (50 uL) extracted from KAB8-7 at 13:20

TLC of reaction mixtures (1)
TLC of KAB8-7 reaction mixture (2)

TLCs were eluted with EtOAc/hexane, 4:1, v/v. Stain: KMnO4

KAB8-8 taken off @ 12:50.
KAB8-7 taken off @ 13:25.

The reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL) and the organic layer removed. The alkaline aqueous fraction was extracted with EtOAc (3 × 30 mL). The organic layers were combined, dried over magnesium sulfate, filtered, then concentrated under reduced pressure to give the crude products.

Crude KAB8-7: 132.7 mg, 175% - yellowish gum + yellow oil.
Crude KAB8-8: 89.4 mg, 118% - yellowish solid gum.

Recrystallisation
30/01/12. The crude products of KAB8-7 and KAB8-8 were dissolved in a minimum of hot EtOAc. Hexane was added dropwise until a white precipitate began to form on contact with the hot, yellow EtOAc solution (~1:1, EtOAc/hexane, v/v). The flasks were sealed then placed in the freezer overnight.
31/01/12. Formation of yellow crystals for both KAB8-7 and KAB8-8. Still stored in freezer.
KAB8-7 crystals on 31/01/12
KAB8-8 crystals on 31/01/12

01/02/12. The KAB8-8 and KAB8-7 crystals were washed with hexane and filtered to give small orange crystals.
KAB8-7 - 102 mg, 83%.
KAB8-8 - 69.2 mg, 91%.
Left: KAB8-7; Right: KAB8-8

02/02/12. 1H-NMR of the KAB8-8 and KAB8-7 samples confirmed both products as the dimethoxy N-benzoyl PZQ analogues. TLC of the crystals showed no co-spotting and the spot that was visible under long wave UV (350 nm) was no longer present.

TO DO:
- TLC crystals against filtrate (see where long wave UV spot ends up).

Summary and Conclusion


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NOTES 30/01/12
- KAB8-8 with the lower catalyst loading probably finished first because of the way I added the acid. The acid solution was added into the MNR10-1/toluene solution with a long needle. The KAB8-7 acid was added to the flask, but not directly into the solution.
- The KAB8-8 mixture went to temperature faster; reached temperature in less than 2 min. The KAB8-7 reaction mixture did not reach 90 °C. The reaction was quenched at ~80 °C.

NOTES 31/01/12
- KAB8-8 filter paper: 1.0973 g

NOTES 01/02/12
- KAB8-7 filter paper 1.1030 g

NOTES 02/02/12
- Long wave co-spot was absent. Will TLC filtrate.
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Linked Posts
Attached Files
Scheme KAB8-X
Scheme KAB8-X
TLC of reaction mixtures (1)
TLC of KAB8-7 reaction mixture (2)
KAB8-7 just removed from heat
KAB8-7 crystals on 31/01/12
KAB8-8 crystals on 31/01/12
Left: KAB8-7; Right: KAB8-8