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9th June 2010 @ 03:48
Preparation of starting material for the Ugi reaction

Reaction Scheme


Table1


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

Start time: 11:05 AM 09/06/2010
End time: 10:45 AM 10/06/2010

To a mixture of phenethylamine (1.00 g, 8.25 mmol), benzyltriethylammonium chloride (TEBACl) (94 mg, 413 µmol, 5 mol%) and NaOH (1.32 g, 33.0 mmol, 4 eq.) in DCM (20 mL) was added chloroform (1.48 g, 1.0 mL, 12.4 mmol, 1.5 eq.) and heated to reflux.
- after 12 h the solution was cooled to room temperature and stirred vigorously for another 12 h.

Work-up: quenched with water, extracted with DCM, washed with 1 N aq. HCl-solution, dried over magnesium sulfate, concentrated.
- dark brown oil, purification by column chromatography (silica gel, hexane/EA, 4:1, stain: KMnO4), Rf = 0.50 (fast elution), TLC (hexane:EA, 4:1, stain: KMnO4).

Result:
Product MW34-1: 633 mg (4.82 mmol, 58%) brown liquid, pungent smell; reference yield : 60% [1]

This patented procedure offers a convenient access for the synthesis of 2-Phenylethyl isocyanide in 1 step. Compound also commercially available

--> upscale reaction MW34-2
See also:
Preparation of 2-phenylethyl isocyanide - alternative route (MW34-3)

Analytical data:
Rf (hexane:EA, 4:1) = 0.50.
1H NMR (CDCl3, 200 MHz): δ = 2.95-3.02 (m, 2H), 3.57-3.65 (m, 2H), 7.21-7.39 (m, 5 H).
13C NMR (CDCl3, 50.3 MHz): δ = 35.6, 42.9, 127.2, 128.7 (2C), 128.7 (2C), 136.7, 156.6.
IR (neat): nu =3031 cm-1, 2147, 1454, 746, 697, 577, 496.
C9H9N (131.2).


References:
[1] “Novel Synthesis of Praziquantel“, A. Dömling, Patent Application 2009, WO 2009/11533(A1), Language: German.

[2] "Synthesis, Biological Evaluation, and Molecular Docking of Ugi Products Containing a
Zinc-Chelating Moiety as Novel Inhibitors of Histone Deacetylases", A. Grolla, V. Podesta`, M. G. Chini, S. Di Micco, A. Vallario, A Genazzani, P. L. Canonico, G. Bifulco, G. C. Tron, G. Sorba and T. Pirali, J. Med. Chem. 2009, 52, 2776–2785.
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Attached Files
Reaction Scheme
Table1
1H NMR MW34-1
1H NMR MW34-1 JCAMP-DX
IR MW34-1
13C NMR MW34-1
13C NMR MW34-1 JCAMP-DX
IR MW34-1