All Blogs | Help | Support | About
20th July 2010 @ 08:40
Low yield and purity in the previous experiment -> see MW43-1

Preparation of a strong Brønstedt-acidic achiral thiourea-catalyst, intended for determination and optimization of the reaction conditions for Pictet-Spengler reactions

Reaction Scheme


Table2


Hazard and Risk Assessment:
Reaction Class: 3
Hazards: T+ very toxic, C Corrosive, F Flammable
Risk rating: U = Unlikely
Start time: 8:00 PM 19/07/2010
End time: 10:00 AM 21/07/2010

Procedure: [1]
To a solution 3,5-bis(trifluoromethyl)aniline (1.51 g, 6.60 mmol, 1.02 mL, 2.2 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) over a period of 30 min at – 5°C. After the addition the ice bath was removed and the mixture was stirred for 36 h at room temperature.
- reaction control after 22 h by TLC (hexane:EA = 10:1, stain: KMnO4): still remaining isothiocyanate (intermediate)

Work-up: quenched with water, separated layers, extracted two times with Et2O, washed with 0.5 N HCl and brine, dried over NaSO4, concentrated (yellow-brown solid).

Recrystallization from CHCl3:
- 1. Crystallization: 649 mg (1.30 mmol, 43%) of colorless, needle-shaped crystals, m.p. 177-178°C (ref. 172-173°C [1]; 180-181°C [2])
1H NMR: no impurities Data: 1H NMR MW43-2
- 2. Crystallization: 465 mg (929 µmol, 31%) of pale brown needle-shaped crystals
1H NMR: no impurities Data: 1H NMR MW43-2b
- Remain: dark brown oil, precipitate in the cold

Results:
-overall yield of N,N’-bis[3,5-bis(trifluoromethyl)phenyl]thiourea MW43-2:1.11 g (2.23 mmol, 74%) (ref. 84%, upscaled reaction)[1]
- small remain of product in the mother liquor
- longer reaction time than reported in the reference increases the yield
- acidic work-up removes remaining amine from the reaction mixture
- one-time recrystallization from chloroform is enough, obtained purity is satisfying


Analytical data:
m.p. 177-178°C (ref. 172-173°C [1]; 180-181°C [2])
Rf (hexane:ethyl acetate = 10:1, stain: KMnO4) = 0.26.
1H NMR (DMSO-d6, 200 MHz) : δ = 10.67 (s, 2H), 8.21 (s, 4H), 7.86 (s, 2H). [2]
Data: 1H NMR MW43-2
1H NMR (MeOD-d4, 200 MHz) : δ = 8.21 (s, 4H), 7.73 (s, 2H), no NH-signals visible, NMR data doesn’t match with reference [1]
Data: 1H NMR MW43-1 (MeOD)
13C NMR (DMSO-d6, 100 MHz): δ = 117.80 (2C), 123.24 (q, J(CF) = 274 Hz, 4C), 124.13 (q, J(CF) = 4 Hz, 4C), 130.43 (q, J(CF) = 33 Hz, 4C), 141.20 (2C), 180.63. Data: 13C NMR MW43-2
IR (neat): nu = 3211 cm-1, 3179, 3051, 1552, 1464, 1373, 1278, 1174, 1127, 889, 679.
Data: IR MW43-1b
MS (ESI (+)) m/z (%): 696 (100) ?, 501 [M+H]+ (5).
HRMS (ESI (+)) Calcd. for [C17H9F12N2S]+: 501.0289, found: 501.0293.
C17H8F12N2S (500.3).

References:
[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.

[2] “Synthetic Studies toward Aryl-(4-aryl-4H-[1,2,4]triazole-3-yl)-amine from 1,3-Diarylthiourea as Urea Mimetics”, A. Natarajan, Y. Guo, H. Arthanari, G. Wagner, J. A. Halperin and M. Chorev, J. Org. Chem. 2005, 70, 16, 6362–6368; DOI: 10.1021/jo0508189.

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.
Linked Posts
This post is linked by:
Attached Files
Table2
1H NMR MW43-2
1H NMR MW43-2b
13C NMR MW43-2
13C NMR MW43-2 JCAMP-DX