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22nd January 2012 @ 22:17
*****Experiment concluded on 27/01/12

Attempt at the AgOTf and Cu(OTf)2 catalysed Pictet-Spengler reactions to give racemic PZQ. This method was previously applied to the synthesis of the electron rich dimethoxy N-benzoyl PZQ analogue (see KAB8-3 and KAB8-4).

Scheme

NOTE: Scheme should say 110 °C AND KAB3-X instead of "KAB8-X"




Hazard and Risk Assessment
Hazard and Risk Assessment


Previous Related Experiments
The copper(II) triflate catalysed PS to give the dimethoxy N-benzoyl PZQ analogue (KAB8-3)
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)

Following Experiments


Procedure
Start: 23/01/12
Finish: 27/01/12

KAB5-1 was dissolved in toluene before the addition of the metal triflate after which the mixture was stirred and heated to 110 °C.

KAB3-9 Amounts Added:
KAB5-1: 0.2153 g, 53.2 mmol
Toluene: 84 mL
AgOTf: 79.0 mg, 58 mol%
Start time: 09:22
KAB3-9 reaction mixture at 30 min
KAB3-9 reaction mixture at ~2.5 hr
KAB3-9 reaction mixture ~5 hr
KAB3-9 reaction mixture at ~7 hr
KAB3-9 reaction mixture at ~23 hr

KAB3-9 reaction mixture at 29 hr
KAB3-9 reaction mixture at 2 days


KAB3-10 Amounts Added:
KAB5-1: 0.1953 g, mmol
Toluene: 77 mL
Cu(OTf)2: 105.0 mg, 60 mol%
Start time: 09:40
KAB3-10 reaction mixture at 15 min
KAB3-10 reaction mixture at 1 hr
KAB3-10 reaction mixture at ~2 hr
KAB3-10 reaction mixture ~4.5 hr
KAB3-10 reaction mixture at ~7 hr

KAB3-10 reaction mixture at ~23 hr
KAB3-10 reaction mixture at ~29 hr
KAB3-10 reaction mixture at 2 days

The reaction progress was monitored by TLC against the starting material (KAB5-1) and the expected product, PZQ. Aliquots (0.1 mL) were extracted from the reaction mixtures and TLC'd undiluted in EtOAc/hexane, 4:1, v/v with a KMnO4 stain (TLC 1 & 2). Eluent for TLC 3+ was EtOAc/hexane, 3:1, v/v.

23/01/12
10:25 - Aliquot 1
11:45 - Aliquot 2
13:15 - Aliquot 3
14:25 - Aliquot 4
16:15 - Aliquot 5
17:55 - Aliquot 6

24/01/12
08:30 - Aliquot 7
11:55 - Aliquot 8
16:05 - Aliquot 9

25/01/12
08:55 - Aliquot 10
13:34 - Aliquot 11

Monitoring the reaction progress by TLC

TLC of reaction mixture (1)
TLC of reaction mixtures (2)
TLC of reaction mixtures (3)
TLC of reaction mixtures (4)
TLC of reaction mixtures (5)

TLC of reaction mixtures (6)
TLC of reaction mixtures (7)
Aliquot 7 of KAB3-9 (left) and KAB3-10 (right)
TLC of reaction mixtures (8)
TLC of reaction mixtures (9)

TLC of reaction mixtures (10)

TLC Legend: (3-9) = Aliquot of the reaction mixture KAB3-9, specified by the number circled at the bottom; (3-10) = Aliquot of the reaction mixture KAB3-10, specified by the number circled at the bottom; (SM) = Starting material KAB5-1; (PZQ) = praziquantel
NOTE - TLC 6 & 7: the pencilled marks were the spots visible under long wave UV.
NOTE - TLC 8: Eluent was EtOAc/hexane, 1:1, v/v, and the TLC was run twice to the solvent line.

TLC 2 suggested incomplete consumption of the SM in both reaction mixtures. Both reaction mixtures contained spots with Rf's below the expected product, PZQ. Reaction mixture KAB3-10 also contained a spot with a higher Rf than the starting material, with an approximate value to the known enediamide intermediate. The low circled spots in KAB3-10 were clearly visible under long wave UV light and were absent in the KAB3-9 reaction mixture.

25/01/12
After stirring at 95-140 °C for 50 hours, the KAB3-10 reaction mixture was allowed to cool. The dark, red-brown, mixture was washed with citric acid (0.5 M, 50 mL) and the aqueous layer removed. The organic layer was then quenched with saturated sodium bicarbonate solution (50 mL).
KAB3-10 reaction mixture after removal from heat

The organic fraction was set aside and the alkaline aqueous layer extracted further with EtOAc (3 × 30 mL, 1 × 50 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give crude KAB3-10 as a dark reddish-brown mixture of solid and liquid.
Crude KAB3-10


The TLC of aliquot 11 of the KAB3-9 reaction mixture suggested the reaction had ceased to progress from the enediamide intermediate. The intensity of higher Rf spots appeared to be increasing. This suggested either consumption of the catalyst (complexation?) or decomposition of the reaction components, which prompted termination of the reaction at 15:40. The KAB3-9 reaction mixture was removed from heat and allowed to cool before the clear, bright yellow solution was transferred to a separating funnel then washed with citric acid (0.5 M, 50 mL).
Washing KAB3-9 with citric acid

The clear, colourless aqueous layer was removed and the yellow organic layer was quenched with saturated sodium bicarbonate solution (50 mL), which turned the organic layer cloudy yellow. Some gas was released. The organic fraction was set aside an the aqueous layer was extracted with EtOAc (3 × 30 mL). The organic layers were combined, dried over magnesium sulfate, then concentrated in vacuo to give crude KAB3-9 as a dark yellow oil.
Crude KAB3-9



TO DO:
- Write down reaction termination time.
- TLC final crude products.
- Calculate rough yield.
- Write conclusion.


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


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NOTES 23/01/12
- The copper solution went a golden brown within 10 minutes of refluxing. This colour change didn't happen previously (when making KAB8-3), but then this is also a different starting material and the reaction is at 110 °C instead of rt.
- The silver solution is either the same or very similar colour to the KAB8-4 experiment. Difficult to tell with the colour of the oil.
- 11:45: KAB3-9 has gone golden in colour, KAB3-10 has gone almost black. Possibly overheated the reaction mixtures?
- TLC 4: I'm not sure what's going on (by TLC). The KAB3-9 reaction mixture is going slightly red, the KAB3-10 reaction mixture is getting darker in colour. There may be some intermediate in the reaction mixtures (the highest Rf spot) but all the other spots are unknown.
- As of ~16:00 there was some (black?) debris, settled in the bottom of the KAB3-10 reaction mixture, not stirring. May be stuck to the bottom.

NOTES 24/01/12
- 08:43: not sure what's going on in the copper solution (KAB3-10), however, both solutions show signs of the enediamide intermediate. The silver reaction (KAB3-9) seems to be much cleaner, but that may be due to problems with the temperature controller of the KAB9-10 reaction (i.e. spiked at 140 C last night).
- 16:33: will leave reaction to run overnight, again.

NOTES 25/01/12
- Uncontrolled temperature controller spiked the temperature at >150 °C. Most likely the cause of the decomposed reaction components.
- The acidic KAB3-10 aqueous layer was yellow. The basic aqueous layer was green, suggesting it contained the copper.
- So far, I suspect AgOTf is acting as a homogenous catalyst and Cu(OTf)2 is acting heterogenously. Unsure of integrity of AgOTf, but the copper appears to be sensitive to decomposition/consumption/reactivity? (i.e. turns from blue to green).

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Linked Posts
Attached Files
Scheme KAB3-X
Table KAB3-9
Table KAB3-10
Hazard and Risk Assessment
KAB3-10 reaction mixture at 15 min
KAB3-9 reaction mixture at 30 min
TLC of reaction mixture (1)
KAB3-10 reaction mixture at 1 hr
KAB3-10 reaction mixture at ~2 hr
KAB3-9 reaction mixture at ~2.5 hr
TLC of reaction mixtures (2)
TLC of reaction mixtures (3)
KAB3-9 reaction mixture ~5 hr
KAB3-10 reaction mixture ~4.5 hr
TLC of reaction mixtures (4)
TLC of reaction mixtures (5)
KAB3-9 reaction mixture at ~7 hr
KAB3-10 reaction mixture at ~7 hr
TLC of reaction mixtures (6)
TLC of reaction mixtures (7)
KAB3-10 reaction mixture at ~23 hr
KAB3-9 reaction mixture at ~23 hr
Aliquot 7 of KAB3-9 (left) and KAB3-10 (right)
TLC of reaction mixtures (8)
KAB3-9 reaction mixture at 29 hr
KAB3-10 reaction mixture at ~29 hr
TLC of reaction mixtures (9)
TLC of reaction mixtures (10)
KAB3-9 reaction mixture at 2 days
KAB3-10 reaction mixture at 2 days
TLC of KAB3-9 reaction mixture (11)
KAB3-10 reaction mixture after removal from heat
Crude KAB3-10
Crude KAB3-9
Washing KAB3-9 with citric acid