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30th January 2012 @ 23:47
*[i]PS = Pictet-Spengler[/i] Concluded on 06/02/12. [b][u]Background[/b][/u] Preparing the enediamide for future acid catalysed reactions to give PZQ. The second and final cyclisatiton step to give PZQ from the enediamide does not require the loss of ethoxy groups, which may reduce side reactions and result in cleaner reactions. [b][u]Hazard and Risk Assessment[/b][/u] [data]2679[/data] [b][u]Previous Related Experiments[/b][/u] [blog]3850[/blog] [blog]3607[/blog] [b][u]Following Experiments[/b][/u] [b][u]Procedure[/b][/u] KAB5-1 (1.80 g, 4.45 mmol) was dissolved in stirred toluene (45 mL) before the solution was cooled in a brine ice bath. Methanesulfonic acid (MSA, 0.63 mL, 4.45 mmol, 1 eq) was added to 0.1 M at 0 °C. The reaction mixture was stirred at rt from 11:45. [data]2681[/data][data]2687[/data] TLC taken at 12:00 (+75 min) and indicated complete consumption of the starting material (KAB5-1), formation of the enediamide (KAB13-1) and some completely cyclised product (to give PZQ). The reaction was immediately terminated by quenching with saturated sodium bicarbonate solution (50 mL) following dilution of the reaction mixture with EtOAc (25 mL). [data]2691[/data][data]2693[/data] The organic layer was set aside and the aqueous fraction further extracted with EtOAc (3 × 30 mL). The organic layers were combined and the bright yellow solution dried over magnesium sulfate. After removal of the drying agent by filtration, the yellow solution was concentrated [i]in vacuo[/i] to give crude KAB13-1 as a yellow oil (2.144 g). [data]2695[/data][data]2697[/data][data]2699[/data][data]2701[/data] [b]Purification[/b] The crude KAB13-1 was purified by silica gel column chromatography, eluting in 60-75% EtOAc in hexane, and monitoring by TLC. The product eluted in fractions 6-16, which were then combined and concentrated under reduced pressure. The yellow oil rapidly crystallised on standing (wet yield 270 mg). The flask was sealed and put in the freezer to promote crystallisation. [data]2739[/data] Fractions 1-5 and 17-30 were separately combined and concentrated under reduced pressure. The KAB13-1 main spot (frac 17-30) was stored in the freezer. [u][b]Summary and Conclusion[/b][/u] The use of MSA was inappropriate and resulted in side reactions, decomposition of reaction components and poor yield. Use metal triflates for future preparations of the PZQ enediamide intermediate. ----------------------------------------------------------------------------- NOTES 31/01/12 - I should have just used silver triflate to do this reaction, and not MSA. It would have been cleaner, with higher yield and I would likely not have required to column the product. -----------------------------------------------------------------------------
Attached Files
Scheme KAB13-1
Scheme KAB13-1
Hazard and Risk Assessment KAB13-1
Reaction mixture at 5 min
Table KAB13-1
Reaction mixture at 1 hr
TLC of reaction mixture at 1 hr
Dilution with EtOAc
Quenched with NaHCO3
First extraction with EtOAc
Left: aqueous fraction; Right: combined organic layers
Organic layers after drying
Crude KAB13-1
Concentrated combined fractions 6-16