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20th July 2010 @ 09:40
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.
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15th July 2010 @ 06:05
Testing various intermediates of PZQ (derivatives) with a achiral Bronstedt-acidic thiourea catalyst MW43-1 as pretest for chiral derivatives of the catalyst - NMR-monitored experiments

Reaction Scheme


Table1


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

Start time: 4:30 PM 15/07/2010
End time: 10:30 PM 16/07/2010

General Procedure:
Each of the compound MW7, MW29-4, MW14, MW40-1 (75.0 µmol) shown in Table1 was solved in CDCl3 (~0.5 mL) in a NMR tube and MW43-1 (3.8 mg, 8.0 µmol, 10 mol%) was added and heated to 60°C for 18h.

MW44-1 – MW44-4: no conversion was monitored (by 1H NMR)

-> MeSO3H was added (5.2 µL of a 5% solution in CDCl3, 384 µg, 4.0 µmol, 5 mol%)
After 4 h at r.t. no conversion was monitored -> heated to 60°C

Comparison of the Reaction NMRs
Data: 1H NMR comparison MW44-1
Data: 1H NMR comparison MW44-2
Data: 1H NMR comparison MW44-3
Data: 1H NMR comparison MW44-4

Results:
No conversion of the starting material was observed
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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

Reaction Scheme


Table1


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: 2:30 PM 09/07/2010

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 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: IR MW43-1a
- further purification of the recrystallized fraction and the remaining brown solid by column chromatography (hexane:EA = 10:1)

Result:
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.

Analytical data:
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: 1H NMR MW43-1 (DMSO)
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)
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).

-> 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:MW43-2


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.
Attached Files
6th July 2010 @ 11:12
Attempts to cleave the protection group of the dimethoxy acetal under acidic conditions – formation of the aldehyde or cyclisation products as an intermediate of the Pictet-Spengler cyclisation?

See also: Attempts to the acid-mediated Pictet-Spengler cyclization of the ‘Ugi intermediate’ MW29 (MW31)

Reaction Scheme correction


Table1


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

Start time: 3:30 PM 05/07/2010
End time: 7:30 PM 05/07/2010

The hydrochloride MW7 (50.0 mg, 165 µmol) was dissolved in various acids or acidic solutions as shown in Table1. The mixtures were stirred for 4 h at room temperature, quenched with water, basified with 2 N aq. NaOH to pH 12 and extracted with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated.

TLC (EA:MeOH:Et3N, 10:1:0.1; stain: Ceric ammonium molybdate)
TLC1


MW42-1:
Starting material reisolated: 38 mg (143 µmol, 87%)
Data: 1H NMR MW42-1

MW42-2:
Hemiaminal 15 mg (68.2 µmol, 41%), complete conversion of the starting material
Data: 1H NMR MW42-2
Data: 13C NMR MW42-2
hemiaminal


MW42-3:
Starting material reisolated: 42 mg (158 µmol, 96%)
Data: 1H NMR MW42-3

MW42-4:
Mixture of compounds, partial conversion to praziquanamine: 28 mg
Data: 1H NMR MW42-4

MW42-5:
Praziquanamine 19 mg (94.1 µmol, 57%), complete conversion of the starting material
Data: 1H NMR MW42-5
Data: 13C NMR MW42-5
praziquanamine


First results:
- The cleavage of the acetal needs strong acidic conditions. With 1 N HCl or a 50% aq. solution of TFA (at room temperature) only staring material could be reisolated.
- Concentrated hydrochloric acid cleaves the acetal and the formed aldehyde cyclizes to the hemiacetal
- conc. methanesulfonic acid forms the Pictete-Spengeler product praziquanamine, less concentrated acid needs longer reaction time / higher reaction temperatures (products?)


Continuation:

Table2


Start time: 2:10 PM 09/07/2010
End time (Trial MW42-2A, -7): 4:15 PM 09/07/2010
End time (Trial MW42-4A, -4B,- 6): 12:20 PM 10/07/2010

MW42-6:
2 N HCl, 22 h at r.t.
Starting material reisolated: 38 mg (143 µmol, 79%)

MW42-7:
6 N HCl, 2 h at r.t.
Starting material reisolated: 40 mg (150 µmol, 91%)

MW42-2A:
conc. HCl, 2 h at room temperature
hemiaminal 19 mg (86.2 µmol, 52%); clean conversion, only traces of impurities

MW42-4A:
10% MeSO3H in wet CHCl3, 22 h at room temperature
PZQamine 23 mg (114 µmol, 69%), small impurities, no starting material visible
1H NMR: 1. spectrum with remaining ethyl acetate, 2. spectrum: broad signals

MW42-4B:
10% MeSO3H in CHCl3, 22 h at 60°C
PZQamine (?) 27 mg, complete conversion of the starting material
NMR: very broad signals -> side products?

Summary:
- fast (tested) cleavage of the dimethoxy acetal function only with conc. HCl solution at room temperature, even 6 N HCl obtains only starting material after 2 h at r.t.

- 10% MeSO3H solution in CHCl3 (~ 1.7 N) leads to a selective cleavage of the acetal and a subsequent Pictet-Spengler cyclisation to praziquanamine after 22 h at r.t., higher concentrations or higher temperatures reduce the conversion time. Wet chloroform (in general: wet organic solvents?) doesn’t influence the formation of praziquanamine – no hemiaminal was observed!
Attached Files
2nd July 2010 @ 08:40
NMR-monitored experiments - testing various intermediates of PZQ (derivatives) with a strong achiral Bronstedt-acid as pretests for chiral derivatives of the catalyst

Reaction Scheme


Table1


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

Start time: 6:15 PM 02/07/2010
End time: 4:00 PM 08/07/2010

General Procedure:
Each of the compound MW7, MW29-4, MW14, MW40-1 (75.0 µmol) shown in Table1 was solved in CDCl3 (~0.5 mL) in a NMR tube and MW39-2 (1.8 mg, 4.0 µmol, 5 mol%) was added.
- after 3 days at r.t no conversion was monitored (by 1H NMR)
- heated to 60°C for further 3 days -> no conversion of the starting material

MW41-1A – MW41-4A
-> addition of MeSO3H (5.2 µL of a 5% solution in CDCl3, 384 µg, 4.0 µmol, 5 mol%) as a Broensted-acidic co-catalyst [reaction index A]
-> reference experiments: MeSO3H (5.2 µL of a 5% solution in CDCl3, 384 µg, 4.0 µmol, 5 mol%). [reaction index B]

Table2


Start time: 5:30 PM 08/07/2010
End time: 4:00 PM 12/07/2010

After 16.5 h at r.t. - no conversion monitored by NMR
-> heated to 60°C for 3 d

Results:
MW41-1A/MW41-1B and MW41-3A/MW41-3B:
No conversion of the starting material monitored

MW41-2A/MW41-2B
About 50% conversion in both trials, no significant difference to the reference experiment

MW41-4A/MW41-4B
Nearly complete conversion of the starting material, but the reference experiment showed a better consumption!


Summary:
The BINOL-N-triflyl phosphoramide catalyst MW39-1 showed no activity (for 5 mol% catalyst loading) for an acid-catalysed Pictet-Spengler reaction of the tested compounds. An additional strong Broenstedt-acid MeSO3H, intended as a co-catalyst, didn’t influence the catalytic activity of the phosphoramide MW39-1. The conversion of MW29-4 and MW40-1 (experiments MW41-2A/MW41-2B and MW41-4A/MW41-4B) was caused by the added MeSO3H, but only the N-cyclohexanoyl-protected amines showed a consumption of the starting material, the free amines MW7 and MW14.
Attached Files