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19th January 2012 @ 00:37
Concluded on 24/01/12

Performed simultaneously with The silver(I) triflate catalysed PS to give the dimethoxy N-benzoyl PZQ analogue (KAB8-4)

Background
Previous experiments KAB11-1, KAB11-2 and KAB11-3 were intended to isolate the enediamide intermediate of the Pictet-Spengler (PS) reaction to give the dimethoxy N-benzoyl PZQ analogue (i.e. KAB8), using catalytic amounts of metal triflates; see also ref [1].
The reaction of the peptide acetal starting material in the stoichometric acid-mediated PS resulted in rapid formation of the expected product (<30 min, see KAB8-1). It was expected that use of proton deficient metal triflates would result in the partial PS to give the iminium ion, which would then tautomerise to the stable enediamide intermediate.
Surprisingly, the reactions KAB11-2 and KAB11-3 produced the complete PS product, the dimethoxy N-benzoyl PZQ analogue (at least, by TLC), in less than 18 hours.
This experiment is an attempt to reproduce the results obtained in the experiment KAB11-3 on a slightly larger scale, in order to determine if the final product is N-benzoyl PZQ analogue.

Scheme
Scheme%20KAB8-3.png
Table%20KAB8-3.jpg

Hazard and Risk Assessment
As for KAB11-3 (here)

Following Experiments

Procedure

19/01/12
MNR10-1 (103 mg, 0.225 mmol) was dissolved in toluene (29 mL) before the addition of Cu(OTf)2 (40.6 mg, 52 mol%) at 11:05, after which the reaction mixture was stirred at room temperature.
A 0.1 mL aliquot was extracted at 13:05. and analysed by TLC (EtOAc/hexane, 4:1, v/v; KMnO4 stain). The sample was not diluted.
TLC of reaction mixture (1)

From left to right:
8-3 = KAB8-3 reaction mixture aliquot 1.
Co = Co-spot of simultaneously run KAB8-3 aliquot 1, the starting material MNR10-1 and the expected product, KAB8-1.
SM = The MNR10-1 starting material
8-1 = The expected product KAB8-1 (made previously)
Co = Co-spot of KAB8-4 reaction mixture aliquot 1, MNR10-1 and KAB8-1.
8-4 = Aliquot 1 of the KAB8-4 reaction mixture.


TLC of reaction mixture (2)

At 16:05 (5 hours), TLC --> completion.
From left to right:
Co = Co-spot of KAB8-3 aliquot 2, the starting material MNR10-1 and the expected product, KAB8-1.
8-3 = KAB8-3 reaction mixture aliquot 2.
SM = The MNR10-1 starting material.
8-1 = The expected product KAB8-1 (made previously).
Co = Co-spot of KAB8-4 reaction mixture aliquot 2, MNR10-1 and KAB8-1.
8-4 = Aliquot 2 of the KAB8-4 reaction mixture.

The reaction mixture was concentrated under reduced pressure, before the residue was dissolved in ethyl acetate to give a pale green solution. The solution was filtered through a silica pad to give a clear filtrate. The filtrate was concentrated under reduced pressure to give (crude?) KAB8-3 as a pale yellow oil, which solidified (crystallised? hard to tell) on standing (12.3 mg)

TLC of crude KAB8-3

From left to right:
8-3 = Crude KAB8-3.
Co = Co-spot of crude KAB8-3 and the expected product
8-1 = The expected product KAB8-1 (made previously).
Co = Co-spot of crude KAB8-4 and the expected product
8-4 = Crude KAB8-4.


Expected product KAB8-3 has Rf = 0.3 in EtOAc/hexane, 4:1, v/v.
Enediamide intermediate (see KAB11-2) has Rf = 0.5 in EtOAc/hexane, 4:1, v/v.

Conclusion
Based on the final TLC of the isolated crude product, it is likely that the product of the reaction KAB8-3 contained a mixture of the enediamide intermediate and the expected product.
The yield and conversion for the procedure is unknown, possibly due to loss of product (may have lost some product by incomplete filtration through silica during the work-up).
The product was not characterised further due to low yield.
On comparison with the simultaneously run AgOTf catalysed PS cyclisation, the Copper(II) triflate may have been more reactive or sensitive to decomposition(?). The copper was also poorly soluble in toluene and by termination of the reaction, turned green and stuck to the bottom of the flask.


References
[1] Todd, M. H., Ndubaku, C. & Bartlett, P. A., J. Org. Chem. 2002, 67, 3985-3988 - DOI: 10.1021/jo010990m (Paper)

Related Experiments
The silver(I) triflate catalysed PS to give the dimethoxy N-benzoyl PZQ analogue (KAB8-4)
Silver(I) triflate catalysed preparation of the dimethoxy N-benzoyl PZQ enediamide (KAB11-2)
Copper(II) triflate catalysed preparation of the dimethoxy N-benzoyl PZQ enediamide (KAB11-3)
Lewis acid catalysed preparation of the dimethoxy N-benzoyl PZQ enediamide (KAB11-1)
Silver(I) triflate catalysed preparation of the dimethoxy N-benzoyl PZQ enediamide (KAB11-2)


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NOTES 19/01/12
- Cu(OTf)2 was in the form of pale blue crystals, which were poorly soluble in toluene.
- Poor work up on my part resulting in loss of product.
- The TLC of the reaction mixture aliquot 2 showed little to no sign of the enediamide intermediate. However, the TLC of the isolated crude product showed a portion of the product was composed of the intermediate.
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Linked Posts
Attached Files
Scheme KAB8-3
Table KAB8-3
Table KAB8-3
TLC of reaction mixture (1)
TLC of reaction mixture (2)
TLC of crude KAB8-3