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30th June 2010 @ 10:24
No product / mixture of compounds in the previous trial: Preparation of (+/-)-BINOL-N-triflyl phosphoramide (MW39) – repetition of the experiment under similar conditions:
Preparation of a strong achiral Brønsted acid, intended for pretests for the acid-catalysed Pictet-Spengler reaction

Reaction Scheme


Table1


Start time: 5:21 PM 29/06/2010
End time: 12:15 PM 30/06/2010

Procedure: [1]
To a mixture of (+/-)-BINOL (172 mg, 600 µmol) and Et3N (585 µL, 425 mg, 4.20 mmol, 7 eq.) in DCM (3 mL) was added POCl3 (110 mg, 67 µL, 720 µmol, 1.2 eq.) and DMAP (147 mg, 1.20 µmol, 2 eq.) at 0°. The mixture was warmed to room temperature and stirred for 1 h.
- evaporated DCM, added propionitrile (3 mL) and TfNH2 MW38 (179 mg, 1.20 mmol, 2 eq.) and heated reaction mixture to 100°C for 18 h

Work-up: quenched with water, extracted with Et2O, washed with aq. NaHCO3 and 4 N HCl, dried over Na2SO4, concentrated
-TLC (ethyl acetate, 100%; stain: KMnO4): Rf = 0.26.
- purification by column chromatography (silica gel; ethyl acetate 100%; Rf = 0.26)

Result:
Product MW39-2: 224 mg pale brown solid (467 µmol, 78%);
- small impurities visible in the 1H NMR (traces of TfNH2 ?)

Analytical data:
Rf (EA, 100%) = 0.26.
1H NMR (CDCl3, 400 MHz) : δ = 2.39 (bs, 1H), 7.10-7.18 (m, 2H), 7.23-7.43 (m, 6H), 7.52-7.58 (m, 2H) 7.73-7.81 (m, 2H).
Data: 1H NMR MW39-2 (400 MHz)
13C NMR (CDCl3, 100 MHz): δ = 120.02 (q, J(CF) = 318 Hz, 1C), 120.25 (2C), 121.02, 121.46, 121.87, 125.52 (2C), 126.50, 126.57, 127.04, 127.16, 128.56 (2C), 131.14 (2C), 131.63, 131.74, 132.22, 132.30, 146.72, 146.80, 147.70, 147.80.
Data: 13C NMR MW39-2
19F NMR (CDCl3, 282 MHz): δ = -79.7.Data: 19F NMR MW39-2
31P NMR (CDCl3, 121 MHz): δ = 16.74.Data: 31P NMR MW39-2
IR (neat): nu = 1288 cm-1, 1203, 1093, 1068, 963, 875, 815, 745, 604, 560.Data: IR MW39-2
MS (ESI (-)) m/z (%): 478 [M-H]-.
HRMS (ESI (-)) Calcd. for [C21H12F3NO5PS]-: 478.0131, found: 478.0134.
C21H13F3NO5PS (479.4).

-> Testing the catalytic activity of N-triflyl phosphoramides for the acid-catalysed Pictet-Spengler reaction: MW41


References:
[1] “Design of Chiral N-Triflyl Phosphoramide as a Strong Chiral Brønsted Acid and Its Application to Asymmetric Diels-Alder Reaction", D. Nakashima and H. Yamamoto, J. Am. Chem. Soc. 2006, 128, 30, 9626–9627.
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25th June 2010 @ 09:05
Varying reaction parameters for the Ugi reaction – temperature, acidic catalyst, stoichiometry, ect. (see MW36-1)

Reaction Scheme


Table1 corrected



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

Start time: 2:32 PM 24/06/2010
End time (MW36-2): 9:30 PM 24/06/2010
End time (MW36-3 - 5): 12:45 PM 25/06/2010

General procedure:
To a mixture of paraformaldehyde (22.9 mg/45.8 mg, 762 µmol/1.52 mmol, 1.0/2.0 eq.), 2,2-dimethoxyethylamine (80.1 mg, 762 µmol, 1.0 eq.), cyclohexanecarboxylic acid (97.7 mg, 762 µmol, 1.0 eq.) and optional p-toluenesulfonic acid (6.6 mg, 38 µmol, 0.05 eq.) or zinc triflate (12.6 mg, 38 µmol, 0.05 eq.) in methanol (1 mL) was added slowly 2-phenylethyl isocyanide MW34 (100 mg, 762 µmol, 105 µL 1.0 eq.) and stirred at room temperature or 60°C, respectively.

Work-up: quenched with water, extraction with ethyl acetate, organic layer washed with 1 N HCl, sat. NaCO3 solution and brine, dried over MgSO4, concentrated.

TLC (EA, 100%, stain: Ceric ammonium molybdate, Rf = 0.45)
TLC1
TLC2 MW34_2 + MW40.JPG


MW36-2:
Heated to 60°C, after 7 h complete conversion of the starting material (TLC, EA 100%)

Work-up: added water -> still an oil
- crude product 295 mg orange-brown high viscous oil
- column chromatography (silica gel, EA 100%)
Result:
Product MW36-2: 241 mg (640 µmol, 84%)
1H NMR: traces of solvent (ethyl acetate)

MW36-3:
Additionally added p-toluenesulfonic acid (6.6 mg, 38 µmol, 0.05 eq.) as a Bronstedt acid, stirred for 22 h at room temperature
Work-up: oil
Result:
- crude yield: 194 mg (493 µmol, 65%) orange-brown oil
Data: 1H_NMR MW36-3: product in high purity – no visible impurities, no further purification needed; traces of solvent (ethyl acetate)

MW36-4:
Additionally added zinc triflate (12.6 mg, 38 µmol, 0.05 eq.) as a Lewis acid, stirred for 22 h at room temperature
Work-up: oil
Result:
Crude yield: 264 mg (671 µmol, 88%) orange-brown oil
Data: 1H_NMR MW36-4: product in high purity – small impurities, no further purification needed; traces of solvent (ethyl acetate)

MW36-5:
2 eq. of paraformaldehyde used, stirred for 22 h at room temperature
Work-up: oil
Result:
Crude yield: 227 mg (577 µmol, 76%) orange-brown oil
Data: 1H_NMR MW36-5: product in high purity – no visible impurities, no further purification needed; traces of solvent (ethyl acetate)


-> Yield improved by heating the reaction, addition of a Lewis-acid and superstoichiometic amount of paraformaldehyde (see MW36-1; yield 57%)
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23rd June 2010 @ 08:45
Ugi-approach to PZQ – synthesis of the non-patented (MeO)2 ‘Ugi-intermediate’ following a patented procedure [1]
Alternative approach to MW32

See also:
Preparation of the Ugi-intermediate via Ugi reaction (MW36-1)
Optimizing conditions for the Ugi reaction (MW36-2 to MW36-5)

Reaction Scheme


Table1



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

Start time: 5:30 PM 23/06/2010
End time: 5:01 PM 24/06/2010

Procedure:
To a mixture of paraformaldehyde (76 mg, 2.54 mmol, 1.0 eq.), 2,2-dimethoxyethylamine (267 mg, 2.54 mmol, 1.0 eq.) and cyclohexanecarboxylic acid (326 mg, 2.54 mmol, 1.0 eq.) in methanol (3 mL) was added slowly 2-(3,4-Dimethoxyphenyl)ethyl isocyanide MW37-1 (489 mg, 2.54 mmol, 1.0 eq.) and stirred at room temperature for 24 h.
-TLC (EA = 100%, stain: Ceric ammonium molybdate, Rf = 0.29): complete conversion of the isocyanide MW37, less side products

TLC1
TLC2


- addition of water: two layers of a liquid and an oil -> no solid precipitate

Work-up: extraction with ethyl acetate, organic layer washed with 1 N HCl, sat. NaCO3 solution and brine, dried over MgSO4, concentrated.
- crude product: 962 mg orange-brown high viscous oil
- purification by column chromatography (silica gel, EA = 100%), Rf (EA, 100%) = 0.25.
- high vac

Result:
Product MW40-1: 805 mg (1.84 mmol, 73%) orange-brown high viscous oil
1H NMR: traces of solvent (ethyl acetate)

-> high-yielded one-step procedure to the ‘Ugi-intermediate’

Analytical data:
Rf (EA, 100%) = 0.25.
1H NMR (CDCl3, 200 MHz): δ = 1.17-1.71 (m, 10H), 2.21/2.54 (m, 1H), 2.66-2.74 (m, 2H), 3.30 (s, 3H), 3.34 (s, 3H), 3.37-3.52, 3.80 (s, 3H), 3.83 (s, 3H), 3.93/3.95 (2H), 4.36/4.52 (t, J=5.0 Hz, 1H), 6.45/6.91 (bs, NH), 6.66-6.76 (m, 3H);rotamers, ratio 1:1.
Data: 1H NMR MW40-1
13C NMR (CDCl3, 75.5 MHz): δ = 25.53, 25.65, 25.74, 29.32, 29.38, 35.22, 40.29/40.62, 40.78/41.03, 50.26/51.52, 52.07/54.02, 55.04, 55.45, 55.90 (2C), 102.83/103.55, 111.39/111.47, 111.80/112.01, 120.55/120.62, 131.04/131.33, 147.73/147.86, 149.09/149.20, 169.25/169.53, 177.78/177.97; rotamers, ratio 1:1.
Data: 13C_NMR MW40-1
IR (neat): nu = 3305 cm-1, 2931, 2855, 1644, 1515, 1418, 1260, 1235, 1124, 1065, 1026, 728.
Data: IR MW40-1
MS (ESI (+)) m/z (%): 895 (100, [M2Na]+), 883 (59), (24, [MNa]+), 405 (34).
HRMS (ESI (+)) Calcd. for [C23H36N2O6Na]+: 459.2466, found: 459.2467.
C23H36N2O6 (436.5).


References:
[1] “Novel Synthesis of Praziquantel“, A. Dömling, Patent Application 2009, WO 2009/11533(A1), Language: German.
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21st June 2010 @ 04:56
Preparation of a strong achiral Brønsted acid, intended for pretests for the acid-catalysed Pictet-Spengler reaction

Reaction Scheme


Table1


Start time: 1:30 AM 21/06/2010
End time: 9:45 AM 22/06/2010

Procedure: [1]
To a mixture of (+/-)-BINOL (172 mg, 600 µmol) and Et3N (585 µL, 425 mg, 4.20 mmol, 7 eq.) in DCM (3 mL) was added POCl3 (110 mg, 67 µL, 720 µmol, 1.2 eq.) and DMAP (147 mg, 1.20 µmol, 2 eq.) at 0°. The mixture was warmed to room temperature and stirred for5 h, instead of 1 h (starting material MW38 needed additional time for another purification step).
- Added propionitrile (3 mL) and TfNH2 MW38 (179 mg, 1.20 mmol, 2 eq.) and heated reaction mixture to 100°C for 15 h

Work-up: quenched with water, extracted with Et2O, washed with aq. NaHCO3 and 4 N HCl, dried over Na2SO4, concentrated

- TLC (hexane:EA = 1:1) Rf = 0.48; TLC (EA 100%) Rf = 0.66; stain: ceric ammonium molybdate, KMnO4, reference: BINOL (B)
TLC1
TLC2
TLC3

- purification by column chromatography (silica gel; hexane:EA = 1:1, then EA 100%)

Result:
51 mg pale brown solid – product??

Analytical data:
1 H NMR & 13C NMR - unspecific signals
19F NMR: signal match to reference [1] Data: 19F_NMR MW39-1
31P NMR: 4 major signals -> mixture?, lowfield shift of the signals compared to reference [1] Data: 31P_NMR MW39-1.jpg
IR - no characteristic signals for SO2 or sulfonamide Data: IR MW39-1
MS -> still waiting for it...


-> repeat experiment MW39-2


References:
[1] “Design of Chiral N-Triflyl Phosphoramide as a Strong Chiral Brønsted Acid and Its Application to Asymmetric Diels-Alder Reaction", D. Nakashima and H. Yamamoto, J. Am. Chem. Soc. 2006, 128, 30, 9626–9627.


Procedure from reference: [1]

General Procedure for Synthesis of Chiral Phosphoramide (2, 3):
To a solution of BINOL derivatives (0.6 mmol) in dichloromethane (3 mL) were added Et3N (585 μL, 4.2 mmol), POCl3 (67 μL, 0.72 mmol) and DMAP (147 mg, 1.2 mmol) at 0 °C. After being stirred for 1 hour at room temperature, EtCN (3 mL) was poured to the reaction and TfNH2 (179 mg, 1.2 mmol) was added at room temperature. Then the reaction was stirred at 100 °C for 12 hours. The reaction was quenched with H2O and extracted with Et2O twice. Combined organic layer was washed with sat. aq NaHCO3, then washed with aq 4N HCl twice. Resultant organic layer was dried over anhydrous Na2SO4, filtered and concentrated. Purification of the crude product by column chromatography on silica gel (eluent: hexane-dichloromethane-Et2O) provided phosphoramide which may be salt. The product was extracted with aq 4N HCl again, dried over anhydrous Na2SO4 and filtered. The concentration of the solution provided the desired phosphoramide.
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18th June 2010 @ 07:56
Starting material for the synthesis of N-triflyl phosphoramides - strong chiral Brønsted acid catalysts for asymmetric Pictet-Spengler reactions [1]

Reaction Scheme correction



Table1 correction



Start time: 3:05 PM 18/06/2010
End time: 4:50 PM 18/06/2010

Procedure: [2]
Ammonia gas (30 mL liquid, 25.4 g, 212 mmol, 15 eq.) was condensed in 3-neck-flask fitted with a dry ice condenser at -78°. Trifluoromethanesulfonic acid (2.4 mL, 4.00 g, 14.2 mmol) was added dropwise over a period of 45 min. . The excess of ammonia was evaporated by allowing the reaction to warm to room temperature.

The colorless and solid remain was purified by sublimation under vacuum:
- first sublimation with a cold finger wasn’t successful – bumping mixture
- Second trial: two flasks connected with a distillation bridge, oil bath temperature: 130 °C, pressure ~ 1mbar

Result:
Product MW38-1: 1.41 g (9.47 mmol, 67%) colorless crystalline solid; yield reference: 89% [1]

Analytical data:
m.p. 118.5-120°C. ref
IR (neat): nu = 3388 cm-1, 3279, 1519, 1352, 1147, 943, 611.


References:
[1] “Design of Chiral N-Triflyl Phosphoramide as a Strong Chiral Brønsted Acid and Its Application to Asymmetric Diels-Alder Reaction", D. Nakashima and H. Yamamoto, J. Am. Chem. Soc. 2006, 128, 30, 9626–9627.

[2] "Synthesis of 3,6-dioxa-Δ7-4-trifluoromethyl perfluorooctyl trifluoromethyl sulfonimide: bis[(perfluoroalkyl)sulfonyl] superacid monomer and polymer", B. H. Thomas, G. Shafer, J. Ji Ma, M.-H. Tu and D. D. DesMarteau, J. Fluorine Chem. 2004, 125, 8, 1231-1240.

[3] "500. Fluorinated sulphonic acids. Part I. Perfluoro-methane-, -octane-, and -decane-sulphonic acids and their simple derivatives", J. Burdon, I. Farazmand, M. Stacey and J. C. Tatlow, J. Chem. Soc. 1957, 2574 - 2578, DOI: 10.1039/JR9570002574.

Procedure from reference: [2]

4.7. Preparation of CF3SO2NH2 (11)

Into a specially fabricated addition funnel which could be
evacuated was placed 61.74 g (218.8 mmol) of (CF3SO2)2O.
To a 250 mL two-necked round bottom flask was condensed
115 g (6.7 mol) of anhydrous ammonia. The flask was
removed from the vacuum line and fitted with the addition
funnel containing (CF3SO2)2O, a magnetic stirrer, and a
drying tube to exclude moisture. The reaction mixture was
placed in a -78 °C bath and the anhydride was added
dropwise over a 2 h period. The excess ammonia was
removed by allowing the reaction to warm to room temperature,
leaving a white solid. The product was purified by
sublimation at 80 8C under vacuum to give 28.96 g
(194.3 mmol) of white crystalline product (89% yield).
19F NMR (CD3CN) d(CF3) -79.4 (3F,s); 1H NMR (CD3CN)
d (NH2) 6.6 (2H,s); IR (solid, KBr pellet) 3379 (s); 3372 (s);
1511 (m); 1348 (s); 1232 (m); 1185 (s); 1155 (m).
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