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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 MW36-1)

Reaction Scheme


Table1 corrected



Hazard and Risk Assessment:
Reaction Class: 2
Hazards: T Toxic, X Irritant, C Corrosive
Risk rating: U = Unlikely

Start time: 2:32 PM 24/06/2010
End time (MW36-2): 9:30 PM 24/06/2010
End time (MW36-3 - 5): 12:45 PM 25/06/2010

General procedure:
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 MW34 (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)
TLC1
TLC2 MW34_2 + MW40.JPG


MW36-2:
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%)
Result:
Product MW36-2: 241 mg (640 µmol, 84%)
1H NMR: traces of solvent (ethyl acetate)

MW36-3:
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
Result:
- crude yield: 194 mg (493 µmol, 65%) orange-brown oil
Data: 1H_NMR MW36-3: product in high purity – no visible impurities, no further purification needed; traces of solvent (ethyl acetate)

MW36-4:
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
Result:
Crude yield: 264 mg (671 µmol, 88%) orange-brown oil
Data: 1H_NMR MW36-4: product in high purity – small impurities, no further purification needed; traces of solvent (ethyl acetate)

MW36-5:
2 eq. of paraformaldehyde used, stirred for 22 h at room temperature
Work-up: oil
Result:
Crude yield: 227 mg (577 µmol, 76%) orange-brown oil
Data: 1H_NMR MW36-5: 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 MW36-1; yield 57%)
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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.