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Pictet-Spengler route to Praziquantel
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25th June 2010 @ 09:05
Varying reaction parameters for the Ugi reaction – temperature, acidic catalyst, stoichiometry, ect. (see[url=http://www.ourexperiment.org/racemic_pzq/321] [b]MW36-1[/b][/url]) [data=size:500x180]242[/data] [data=size:500x180]254[/data] [b]Hazard and Risk Assessment:[/b] Reaction Class: 2 Hazards: T Toxic, X Irritant, C Corrosive Risk rating: U = Unlikely Start time: 2:32 PM 24/06/2010 End time ([b]MW36-2[/b]): 9:30 PM 24/06/2010 End time ([b]MW36-3 - 5[/b]): 12:45 PM 25/06/2010 [b]General procedure:[/b] To a mixture of paraformaldehyde (22.9 mg/45.8 mg, 762 µmol/1.52 mmol, 1.0/2.0 eq.), 2,2-dimethoxyethylamine (80.1 mg, 762 µmol, 1.0 eq.), cyclohexanecarboxylic acid (97.7 mg, 762 µmol, 1.0 eq.) and optional p-toluenesulfonic acid (6.6 mg, 38 µmol, 0.05 eq.) or zinc triflate (12.6 mg, 38 µmol, 0.05 eq.) in methanol (1 mL) was added slowly 2-phenylethyl isocyanide [url=http://www.ourexperiment.org/racemic_pzq/309][b]MW34[/b][/url] (100 mg, 762 µmol, 105 µL 1.0 eq.) and stirred at room temperature or 60°C, respectively. Work-up: quenched with water, extraction with ethyl acetate, organic layer washed with 1 N HCl, sat. NaCO3 solution and brine, dried over MgSO4, concentrated. TLC (EA, 100%, stain: Ceric ammonium molybdate, Rf = 0.45) [data]246[/data] [data]248[/data] [b]MW36-2:[/b] Heated to 60°C, after 7 h complete conversion of the starting material (TLC, EA 100%) Work-up: added water -> still an oil - crude product 295 mg orange-brown high viscous oil - column chromatography (silica gel, EA 100%) [b]Result:[/b] Product [b]MW36-2[/b]: 241 mg (640 µmol, 84%) [url=http://www.ourexperiment.org/data/250.html]1H NMR[/url]: traces of solvent (ethyl acetate) [b]MW36-3:[/b] Additionally added p-toluenesulfonic acid (6.6 mg, 38 µmol, 0.05 eq.) as a Bronstedt acid, stirred for 22 h at room temperature Work-up: oil [b]Result:[/b] - crude yield: 194 mg (493 µmol, 65%) orange-brown oil [data=text]256[/data]: product in high purity – no visible impurities, no further purification needed; traces of solvent (ethyl acetate) [b]MW36-4:[/b] Additionally added zinc triflate (12.6 mg, 38 µmol, 0.05 eq.) as a Lewis acid, stirred for 22 h at room temperature Work-up: oil [b]Result:[/b] Crude yield: 264 mg (671 µmol, 88%) orange-brown oil [data=text]258[/data]: product in high purity – small impurities, no further purification needed; traces of solvent (ethyl acetate) [b]MW36-5:[/b] 2 eq. of paraformaldehyde used, stirred for 22 h at room temperature Work-up: oil [b]Result:[/b] Crude yield: 227 mg (577 µmol, 76%) orange-brown oil [data=text]260[/data]: product in high purity – no visible impurities, no further purification needed; traces of solvent (ethyl acetate) -> Yield improved by heating the reaction, addition of a Lewis-acid and superstoichiometic amount of paraformaldehyde (see [url=http://www.ourexperiment.org/racemic_pzq/321][b]MW36-1[/b][/url]; yield 57%)
Attached Files
Reaction Scheme
Table1
TLC1
TLC2 MW34_2 + MW40.JPG
1H NMR MW36-2
1H NMR MW36-2 JCAMP-DX
Table1 corrected
1H_NMR MW36-3
1H_NMR MW36-4
1H_NMR MW36-5
Comments
Re: Optimizing conditions for the Ugi reaction (MW36-X) by Matthew Todd
27th June 2010 @ 00:17
Michael, is this MW36 or MW34? The title/table/text don't match. Also, Jean-Claude raises a question about the NMR correspondence with the literature: http://ff.im/mHiUF
Re: Optimizing conditions for the Ugi reaction (MW36-X) by Michael Wolfle
28th June 2010 @ 02:34
Oh indeed, it should be the reaction number MW36, not MW34. I mixed it when I was using a previous template of the starting material - Thanks.