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8th July 2010 @ 06:19
Preparation of a strong Brønstedt-acidic achiral thiourea-catalyst, intended for determination and optimization of the reaction conditions for Pictet-Spengler reactions

Reaction Scheme


Hazard and Risk Assessment:
Reaction Class: 3
Hazards: T+ very toxic, C Corrosive, F Flammable
Risk rating: U = Unlikely

Start time: 1:58 PM 08/07/2010
End time: --

Procedure: [1]
To a solution of 3,5-bis(trifluoromethyl)aniline (1.44 g, 6.30 mmol, 977 µL, 2.1 eq.) and Et3N (729 mg, 1.00 mL, 7.20 mmol, 2.4 eq.) in dry THF (50 mL) under argon atmosphere was added dropwise a solution thiophogene (345 mg, 229 µL, 3.00 mmol, 1 eq.) in dry THF (20 mL) at – 8°C. After the addition the ice bath was removed and the mixture was stirred for 24 h at room temperature.

[1] "Acid-free, organocatalytic acetalization", M. Kotke and P. R. Schreiner, Tetrahedron 2006, 62, 2-3, 434-439; doi:10.1016/j.tet.2005.09.079.

Procedure from the reference:
4.1.1. Synthesis of organocatalyst N,N0-bis[3,5-bis(trifluoromethyl) phenyl]thiourea.
For large-scale preparation the synthesis of 1 followed a modified literature protocol.17
In an oven-dried 1000 mL three-necked flask equipped with thermometer, addition funnel, gas inlet, and magnetic stirring bar a mixture of 3,5-bis(trifluoromethyl)aniline (23.39 g, 100 mmol) and triethylamine (16.57 mL, 119 mmol) in THF (720 mL) was prepared. Under argon atmosphere a mixture of thiophosgene (3.29 mL, 43 mmol) in THF (70 mL) was added dropwise to the stirred solution at K5–0 8C. After addition, the yellow suspension (a whitesolid precipitated) was allowed to stir at room temperatureAfter 24 h the bulk of solvent was removed in a rotary evaporator under reduced pressure, the concentrated browncolored residue was added to water (450 mL), and the aqueous layer was extracted with diethyl ether (2!150 mL). The combined organic layers were washed with brine (1!80 mL) and dried over sodium sulfate. After filtration and evaporation of the solvent the red-brown solid crude product was purified by recrystallization from chloroform once, and the resulting slightly yellow solid, was dissolved in a minimum amount of diethyl ether to be re-precipitated by addition of n-hexane as a nearly colorless solid that was dried over Sicapente in a desiccator to obtain spectroscopically pure thiourea derivative 1 (36.1 g, 72 mmol, 84%). Concentrating the mother liquor to a minimum volume and cooling in an ice box afforded an additional amount (2.9 g, 5.8 mmol) of 1.
Mp 172–173 8C; X-ray data,18 IR (KBr): 3207, 3050, 2987, 1555, 1467, 1376, 1326, 1289, 1181, 1133, 930, 891, 714, 701, 684; 1H NMR (400 MHz, [d4] methanol): dZ7.33–7.27 (m, 6H), 7.68 (s, 2H), 13C NMR (100 MHz, [d4] methanol): dZ 120.47 (CH), 123.17 (Cq), 125.87 (CH), 132.67 (Cq), 142.51 (Cq), 182.20 (C]S); HRMS calcd C17H8N2SF12: 500.0216; found: 500.0210; CHN-analysis: calcd C 40.81, H 1.61, N 5.60; found C 40.69, H 1.65, N 5.68.
Attached Files
Reaction Scheme