ourExperiment

3. Step: Preparation of a strong achiral Brønstedt-acid, intended for determination and optimization of the reaction conditions for the acid-catalyzed Pictet-Spengler reaction [1,2]

See also:
1. Step: Preparation of the starting material -> see MW45-1
2. Step: Preparation of 1,1-Binaphthyl-2,2-disulfonate -> see MW45-2





Hazard and Risk Assessment:
Reaction Class: 2
Hazards: C Corrosive, O Oxidizing agent
Risk rating: U = Unlikely
Note: Performic acid has a potential explosive hazard if it comes in contact with metals or their salts and is highly explosive in concentrated form!


MW45-3:
Start time: 7:00 PM 09/08/2010
End time: 10:10 PM 09/08/2010

Procedure: Modification of [2]
30% aq. H2O2 (700 µl) was added to formic acid (7.0 mL) and stirred for 1 h at room temperature. A solution of MW45-2 (50 mg, 109 µmol) in DCM (1 mL) was added dropwise to the formic acid solution and stirred for another 2 h.
Work-Up:
- quenched with 6 N HCl (5 mL), aqueous layer extracted with chloroform and ethyl acetate

-> 1H NMR: no or only traces of product
-> compound couldn’t extracted from the aqueous layer?


MW45-3a:
Repeated procedure of MW45-3:
- 30% aq. H2O2 (700 µl) was added to formic acid (7.0 mL) and stirred for 1 h at room temperature.
- added a solution of MW45-2 (50 mg, 109 µmol) in DCM (1 mL) dropwise and stirred for 2 h.
Work-Up:
- added water (3 mL) to the mixture: colorless solid precipitated
- the mixture was evaporated carefully under reduced pressure and the remaining water was removed by azeotropic distillation with toluene (3 times 5 mL).

-> 1H NMR: undefined aromatic signals
-> decomposition of the product due to a too long reaction time?


MW45-3b:
Start time: 4:10 PM 11/08/2010
End time: 5:40 PM 11/08/2010

Repeated procedure of MW45-3:
- 30% aq. H2O2 (700 µl) was added to formic acid (7.0 mL) and stirred for 1 h at room temperature.
- added a solution of MW45-2 (50 mg, 109 µmol) in DCM (1 mL) dropwise and stirred for 30 min.
Work-Up:
- added water (3 mL) to the mixture: colorless solid precipitated
- the mixture was evaporated carefully under reduced pressure and the remaining water was removed by azeotropic distillation with toluene (3 times 5 mL).

-> 1H NMR: product with impurities, signals match with the 1H NMR data of reference [1]
- large peak at 2.44 ppm (12 H) -> dimethyl ammonium salt as counter ion to the sulfonate?
-> use conditions for up-scaling reaction


MW45-3c:
Start time: 6:10 PM 13/08/2010
End time: 7:30 PM 13/08/2010

Up-scaled procedure of MW45-3:
- a solution of formic acid (20 mL) and 30 % aq. H2O2 (2.0 mL) was stirred for 1 h at room temperature
- added a solution of MW45-2 (434 mg, 109 µmol) in DCM (5 mL) was added dropwise and stirred for 20 min
- TLC (chloroform, 100%; stain: ceric ammonium molybdate) showed a complete consumption of the starting material after 15 min
- quenched with water (15 mL): pale yellow precipitate
- mixture was evaporated under reduced pressure and remaining water was removed by azeotropic distillation with toluene (3 times 5 mL).

-> yellow solid (448 mg)
-> 1H NMR showed a complete and selective conversion to the disulfonic acid / sulfonate, (1H NMR matches with date from reference [1]), but still one singulett peak at 2.55 pm (12H) – dimethyl ammonium something...

- small impurities of side products could removed by dissolving the residue in hot chloroform which obtained a pale yellow solid (407 mg), but still the deprotonated sulfonate with a ammonium counter ion
2. Work-up:
- using a Amberlite IR-120H ion exchange resin to protonate the sulfonate
- dissolved salt in MeOH/H2O (1:1) and passed it through a column of Amberlite IR-120H
- evaporate resulting solution and remove water by azeotropic distillation with toluene



References:
[1] “Pyridinium 1,1′-Binaphthyl-2,2′-disulfonates as Highly Effective Chiral Brønsted Acid−Base Combined Salt Catalysts for Enantioselective Mannich-Type Reaction”, M. Hatano, T. Maki, K. Moriyama, M. Arinobe and K. Ishihara, J. Am. Chem. Soc. 2008, 130, 16858–16860; DOI: 10.1021/ja806875c.

[2] “A Powerful Chiral Counteranion Motif for Asymmetric Catalysis”, P. García-García, F. Lay, P. García-García, C. Rabalakos, B. List, Angew. Chem. Int. Ed. 2009, 48, 4363 –4366; DOI: 10.1002/anie.200901768.

Procedure from the reference: [2]
(R)-3,3'-Bis[3,5-bis(trifluoromethyl)phenyl]-1,1'-binaphthyl-2,2'-disulfonic acid (3): A performic acid solution was prepared by mixing and stirring 30% H2O2 (7.01 mL, 69.6 mmol) and formic acid (70 mL) at room temperature for 1 h. To this solution S-thiocarbamte 13 (2.05 g, 2.32 mmol) in 35 mL dichloromethane was added dropwise. After stirring for 3 h, the solution was filtered over a pad of silica. The filtrate was concentrated in vacuo to furnish the crude product which was subjected to silica gel column chromatography using dichloromethane/methanol (20/1) as eluent.
The resulting Na-salt was dissolved in dichloromethane and washed with 6N HCl. Remaining water traces were removed by azeotropic distillation with toluene to yield 3 (1.57g, 81% yield).

2. step for the preparation of 1,1-Binaphthyl-2,2-disulfonate – a strong achiral Brønstedt-acid, intended for determination and optimization of the reaction conditions for the acid-catalyzed Pictet-Spengler reaction [1,2]

1. step: preparation of the starting material -> see MW45-1



Hazard and Risk Assessment:
Reaction Class: 2
Hazards: T toxic
Risk rating: U = Unlikely

Start time: 1:00 PM 03/08/2010
End time: 2:20 PM 03/08/2010

Procedure: [2]
MW45-1 (500 mg, 1.09 mmol) was placed in a roundbottom flask and heated in a heating mantle to 250°C for 80 min. The dark brown solid was dissolved in chloroform and purified by column chromatography (silica gel, CHCl3; 100%).

References:
[1] “Pyridinium 1,1′-Binaphthyl-2,2′-disulfonates as Highly Effective Chiral Brønsted Acid−Base Combined Salt Catalysts for Enantioselective Mannich-Type Reaction”, M. Hatano, T. Maki, K. Moriyama, M. Arinobe and K. Ishihara, J. Am. Chem. Soc. 2008, 130, 16858–16860; DOI: 10.1021/ja806875c.

[2] “A Powerful Chiral Counteranion Motif for Asymmetric Catalysis”, P. García-García, F. Lay, P. García-García, C. Rabalakos, B. List, Angew. Chem. Int. Ed. 2009, 48, 4363 –4366; DOI: 10.1002/anie.200901768.

Procedure from the reference: [2]
(R)-3,3'-Bis[3,5-bis(trifluoromethyl)phenyl]-1,1'-binaphthyl-2,2'-diyl-S,S'-bis(N,N-dimethylthiocarbamate) (13):
O-Thiocarbamate 12 (2.31 g, 2.61 mmol) was placed into a dram glass vial under argon and heated in a metal block to 250 °C for 80
min. The resulting crude product was purified by column chromatography using hexanes/ethyl acetate (95/5) as eluent to afford 13 (2.19 g, 95% yield).

Intermediate for the preparation of 1,1-Binaphthyl-2,2-disulfonate – a strong achiral Brønstedt-acid, intended for determination and optimization of the reaction conditions for the acid-catalyzed Pictet-Spengler reaction [1,2]





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

Start time: 4:30 AM 02/08/2010
End time: 6:30 PM 02/08/2010

Procedure: [1]
To an ice cooled solution of (+/-)-1,1’-bi(2-naphthol) (1.00g, 3.49 mmol) in dry DMF (10 mL) under argon was added sodium hydride (350 mg, 8.73 mmol, 2.5 eq.; 60% oil dispersion), warmed to room temperature and stirred for 10 min. The resulting yellow solid was slightly heated to obtain a yellow dispersion. To the dispersion N,N-dimethylthiocarbamoyl chloride (950 mg, 7.68 mmol, 2.2 eq.) was added at room temperature and heated to 85°C for 1.5 h.
Work-up:
The yellow-brown mixture was cooled to room temperature and poured into 1% aqueous KOH solution (30 mL). The pale brown solid was filtered off, washed with water and dissolved in DCM. The organic layer was separated from the remaining water, washed with brine and dried over sodium sulfate. After evaporation of the solvent a pale yellow solid was obtained.

Crude product:
1.83 g (3.98 mmol, 114%) pale yellow solid MW45-1,
1H/13C NMR showed a good purity of the product, but remaining DMF
Data: 1H NMR MW45-1 Data: 13C NMR MW45-1

- dissolved product in chloroform and washed 3 times with brine, dried over sodium sulfate and concentrated

Result:
1.50 g (3.26 mmol, 93%) pale yellow solid MW45-1,
1H NMR: DMF could be removed, minor impurities for hexane/mineral oil

-> no further purification for the following step MW45-2


Analytical data: [1]
1H NMR (CDCl3, 200 MHz): δ = 2.51 (s, 6H), 3.07 (s, 6H), 7.25-7.32 (m, 2H), 7.40-7.47 (m, 4H), 7.61 (d, J = 8.8 Hz, 2H), 7.87-8.01 (m, 4H).
Data: 1H NMR MW45-1a
13C NMR (CDCl3, 500 MHz): δ = 38.2 (2C), 42.9 (2C), 123.8 (2C), 124.1 (2C), 125.8 (2C), 126.5 (2C), 126.9 (2C), 127.9 (2C), 128.4 (2C), 131.6 (2C), 133.4 (2C), 149.6 (2C), 186.3 (2C).
Data: 13C NMR MW45-1
IR (neat): nu = 2924 cm-1, 2855, 1665, 1524, 1502, 1385, 1282, 1207, 1129, 1091, 812, 752.
Data: IR MW45-1a
C26H24N2O2S2 (460.6).


References:
[1] “Pyridinium 1,1′-Binaphthyl-2,2′-disulfonates as Highly Effective Chiral Brønsted Acid−Base Combined Salt Catalysts for Enantioselective Mannich-Type Reaction”, M. Hatano, T. Maki, K. Moriyama, M. Arinobe and K. Ishihara, J. Am. Chem. Soc. 2008, 130, 16858–16860; DOI: 10.1021/ja806875c.

[2] “A Powerful Chiral Counteranion Motif for Asymmetric Catalysis”, P. García-García, F. Lay, P. García-García, C. Rabalakos, B. List, Angew. Chem. Int. Ed. 2009, 48, 4363 –4366; DOI: 10.1002/anie.200901768.

Procedure from the reference: [1]
(R)-1,1’-Binaphthalene-2,2’-diyl-O,O’-bis(N,N-dimethylthiocarbamate)
(3):1,2 An ice cooled solution of (R)-BINOL (14.3 g, 50.0 mmol) in 100 mL of distilled DMF under N2 was treated under vigorously stirring with NaH (4.4 g, 110 mmol; 60% oil dispersion). To the resulting yellow solution was added N,N-dimethylthiocarbamoyl chloride (13.6 g, 110 mmol) at 0 °C, and the solution was warmed at 85 °C for 1 h by monitoring with the TLC. Then, the reaction mixture was cooled to room temperature and poured into 1% aqueous KOH (300 mL). The colorless precipitate was filtered, washed thoroughly with water, and dissolved in CH2Cl2.
The CH2Cl2 solution was dried over MgSO4 and evaporated to obtain a colorless solid that was recrystallized from CHCl3/hexane (20.2 g, 88% yield). 1H NMR (300 MHz, CDCl3) δ 2.52 (s, 6H), 3.08 (s, 6H), 7.30 (ddd, J = 8.4, 7.1, 0.9 Hz, 2H), 7.42-7.48 (m, 4H), 7.62 (d, J = 8.7 Hz, 2H), 7.91 (d, J = 8.7 Hz, 2H), 7.97 (d, J = 8.7 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 37.9 (2C), 42.6 (2C), 123.6 (2C), 123.8 (2C), 125.6 (2C), 126.2 (2C), 126.6 (2C), 127.6 (2C), 128.2 (2C), 131.3 (2C), 133.1 (2C), 149.3 (2C), 186.0 (2C). IR(KBr) 2934, 1537, 1394, 1286, 1213, 1136, 1119, 812, 751 cm–1. [α]D
22.8 = +156.1 (c 1.0, CHCl3). HRMS(FAB+) calcd for 26H24N2O2S2 [M]+ 460.1279, found 460.1276.

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





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.

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





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)
-> Add MeSO3H (5.2 µL of a 5% solution in CDCl3, 384 µg, 4.0 µmol, 5 mol%)


Start time: 12:00 AM 16/07/2010

after 4 h at r.t. no conversion was monitored -> heated to 60°C

Data: 1H NMR comparison MW44-1
Data: 1H NMR comparison MW44-2
Data: 1H NMR comparison MW44-3
Data: 1H NMR comparison MW44-4