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28th February 2012 @ 22:19
PS = Pictet-Spengler

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Summary and Conclusion
Successful AgOTf catalysed Pictet-Spengler reaction to give the dimethoxy N-benzoyl PZQ analogue. Isolated yield was 87%. Incomplete isolation of product after 3 recrystallisation crops - some product remained in mother liquor. Recommend column before recrystallisation of product in future attempts to remove the enamide intermediate.
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START: 29/02/12
FINISH: 06/03/12

Background




Hazard and Risk Assessment
Hazard and Risk Assessment KAB8-15


Previous Related Experiments
AgOTf catalysed PS to give the dimethoxy N-benzoyl PZQ analogue (KAB8-10)
The TfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-12)
The silver(I) triflate catalysed PS to give the dimethoxy N-benzoyl PZQ analogue (KAB8-4)

Following Experiments
AgOTf catalysed PS reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-16)
AgOTf catalysed PS reaction to give the dimethoxy PZQ analogue (KAB1-6)

Procedure
Reaction performed under anhydrous conditions. MNR10-2 (618 mg, 1.35 mmol) was dissolved in dry toluene (62 mL) before the addition of AgOTf (33.4 mg, 0.130 mmol, 10 mol%). The reaction mixture was immediately placed in a pre-heated oil bath at 90 °C and refluxed from 09:40 in the dark. The reaction progress was monitored by TLC against the MNR10-2 starting material and the expected product (identical to KAB8-4).
Reaction Setup
Reaction mixture (5 min)


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, MNR10-2 starting material and the expected product, (3)MNR10-2 starting material, (4)Expected product identical to KAB8-4.
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)


Workup Procedure
Four hours after the addition of AgOTf, the reaction mixture was taken out of the oil bath and allowed to cool. The mixture was transferred to a separating funnel then diluted with EtOAc (50 mL).
Reaction mixture after removal from heat
Silver residue stuck in the flask
Dilution with EtOAc

After washing with citric acid solution (0.5 M, 50 mL), the organic fraction was separated. The acidic aqueous fraction was adjusted to pH 10 by the addition of sodium hydroxide solution (2 M) turning the solution a dark grey colour.
Washed with citric acid solution
Acidic aqueous fraction
Aqueous fraction after basification

The aqueous mixture was extracted with EtOAc (3 × 50 mL). The organic fractions were combined then dried over magnesium sulfate, which turned the cloudy orange solution a clear golden colour.
First extraction with EtOAc
Second extraction with EtOAc
Third extraction with EtOAc
Left: aqueous fraction; Right: combined organic layers
Drying combined organic fractions over MgSO4

After removal of the drying agent by filtration, the solution was concentrated under reduced pressure to give crude KAB8-15 as a dark brown sticky oil (657 mg, 133%).
Dried combined organic fractions
Crude KAB8-15


Purification 29/02/12
The crude product was dissolved in minimal EtOAc then filtered through a short silica column. The filtrate was concentrated under reduced pressure to give an off-white foam (509 mg, 103%).
Filtering through silica
Filtered KAB8-15

The foam was dissolved in minimal EtOAc with heating. Hexane was added dropwise until a white precipitate began to momentarily appear as the hexane was added to the solution. The flask was sealed and put in the freezer overnight.

Purification (cont'd) 02/03/12
The white crystals were filtered out and washed with hexane. Crystals continued to form in the filtrate, which was transferred to a weighed container, sealed and put back into the freezer.
Yield so far: 245 mg (50%).

Purification (cont'd) 05/03/12
Filtered crystals then washed with hexane. Product still crashing out. The filtrate was concentrated under reduced pressure and the residue recrystallised with EtOAc/hexane.
Yield so far: 340 mg (69%).

Purification (cont'd) 06/03/12
Crystals were filtered and washed with hexane. TLC of the crystals against the mother liquor suggested product still remained in the mother liquor. The products were taken no further.

Summary and Conclusion
Successful AgOTf catalysed Pictet-Spengler reaction to give the dimethoxy N-benzoyl PZQ analogue. Isolated yield was 87%. Incomplete isolation of product after 3 recrystallisation crops - some product remained in mother liquor. Recommend column before recrystallisation of product in future attempts to remove the enamide intermediate.

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NOTES 29/02/12
- Slightly concerned that good AgOTf (i.e. right out of the bottle) is white. The AgOTf that I've been using up until now has been beige.
- Reaction mixture turned brownish within 5 min. At 15 minutes, very brown - Silver reduced?
- 4 hours. Silver got reduced.
- Flask: 59.4272 g
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Linked Posts
Attached Files
Hazard and Risk Assessment KAB8-15
Scheme KAB8-15
TLC of reaction mixture (5 min)
TLC of reaction mixture (15 min)
TLC of reaction mixture (30 min)
Reaction Setup
Reaction mixture (5 min)
Table KAB8-15
TLC of reaction mixture (1 h)
TLC of reaction mixture (2 h)
TLC of reaction mixture (2 h)
TLC of reaction mixture (3 h)
TLC of reaction mixture (4 h)
Reaction mixture after removal from heat
Silver residue stuck in the flask
Dilution with EtOAc
Washed with citric acid solution
Acidic aqueous fraction
Aqueous fraction after basification
First extraction with EtOAc
Second extraction with EtOAc
Third extraction with EtOAc
Left: aqueous fraction; Right: combined organic layers
Drying combined organic fractions over MgSO4
Dried combined organic fractions
Crude KAB8-15
Filtering through silica
Filtered KAB8-15
Comments
Re: AgOTf catalysed PS reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-15) by Murray Robertson
28th February 2012 @ 22:42
Hazard and Risk Assessment approved, MNR 29/2/12
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