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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 acid-catalyzed Pictet-Spengler reactions [data=size:500x150]325[/data] [data=size:500x150]327[/data] [b]Hazard and Risk Assessment:[/b] 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: 2:30 PM 09/07/2010 [b]Procedure:[/b] [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 22 h at room temperature. Work-up: quenched with water, separated layers, extracted two times with Et2O, washed with 0.5 N HCl and brine, dried over NaSO4, concentrated. - Remaining brown oil was dissolved in CHCl3 and concentrated again -> brown solid - recrystallization from CHCl3 obtained a low yield and low purity - recrystallized twice (from toluene and CHCl3): a colorless solid, but is still a side product (similar properties) First precipitate 340 mg colorless solid (+ unknown side product), m.p. 161-162°C (ref. 172-173°C)[1] [data=text]338[/data] - further purification of the recrystallized fraction and the remaining brown solid by column chromatography (hexane:EA = 10:1) [b]Result:[/b] 1. Fraction: 167 mg (334 µmol, 11%) of a colorless crystalline solid, m.p. 167-168°C. 2. Fraction: 177 mg (354 µmol, 12%) of a colorless solid, impurities visible in the 1H NMR. [b]Analytical data:[/b] m.p. 167-168°C (ref. 172-173°C) [1] Rf (hexane:ethyl acetate = 10:1, stain: ) = 0.26. 1H NMR (DMSO-d6, 200 MHz) : δ = 10.67 (s, 2H), 8.21 (s, 4H), 7.86 (s, 2H). [2] [data=text]342[/data] 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=text]344[/data] IR (neat): nu = 3211 cm-1, 3179, 3051, 1552, 1464, 1373, 1278, 1174, 1127, 889, 679. [data=text]340[/data] MS (ESI (+)) m/z (%): 696 (100) ?, 501 [M+H]+ (5). HRMS (ESI (+)) Calcd. for [C17H9F12N2S]+: 501.0289, found: 501.0293. C17H8F12N2S (500.3). -> overall yield of the N,N’-bis[3,5-bis(trifluoromethyl)phenyl]thiourea MW43-1 is about 24%, low purity and problems with the purification of the thiourea compound - unknown peak in the mass spectrum: m/z = 696 (100%) -> repetition of the experiment:[url=][b]MW43-2[/b][/url] [b]References:[/b] [url=][1] "Acid-free, organocatalytic acetalization", M. Kotke and P. R. Schreiner, [i]Tetrahedron[/i] [b]2006[/b], [i]62[/i], 2-3, 434-439; doi:10.1016/j.tet.2005.09.079.[/url] [url=][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,[i] J. Org. Chem.[/i] [b]2005[/b], 70, 16, 6362–6368; DOI: 10.1021/jo0508189. [/url] [b]Procedure from the reference:[/b] [i]4.1.1. Synthesis of organocatalyst N,N0-bis[3,5-bis(trifluoromethyl) phenyl]thiourea.[/i] 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
IR MW43-1a
IR MW43-1b
1H NMR MW43-1 (DMSO)
1H NMR MW43-1 (MeOD)