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22nd February 2011 @ 09:43
Acid-mediated cyclization of the dimethoxy-N-benzoyl-protected Ugi intermediate MW52-1 with methanesulfonic acid

scheme.png


See:
Acid-mediated Pictet-Spengler of the dimethoxy-N-benzoyl-Ugi intermediate (MW54-1 to MW54-2)

Hazard and Risk Assessment:
HRAF MW53.pdf


Start time: 8:10 PM 22/02/2011
End time: 9:00 PM 23/02/2011

MW52-1 (300 mg, 697 µmol, M.W. 430.5 g/mol) was stirred with methanesulfonic acid (1 mL) for 13 h at 60°C.
- work-up: neutralized with Na2CO3, extracted with DCM, dried with Na2SO4, evaporated
crude yield: 249 mg (680 mmol, 98%)
[M.W. 366.4 g/mol]

-Column (silica gel, ethyl acetate, 100%)
Rf 0.30 (ethyl acetate, 100%)
Yield: 155 mg (423µmol, 61%) colourless solid

Results:
Clean reaction but moderate yield and relatively long reaction time for a Pictet-Spengler reaction under strong acidic conditions and compound which contains 2 activating substituents.


Analytical data:
1H NMR (CDCl3, 200 MHz): delta = 2.63-3.16 (m, 4H), 3.85 (br s, 6H), 4.02-4.36 (m, 2H), 4.85-5.16 (m, 3H), 6.64-6.80 (m, 2H), 7.45 (m, 5H). rotamers, strong signal broadening Data: 1H NMR MW54-3.pdf
1H NMR (CDCl3, 200 MHz, T=323K): delta = 2.63-3.16 (m, 4H), 3.82-3.85 (m, 6H), 4.05 (d, J=17.6 Hz, 1H), 4.49 (br d, J=17.6 Hz, 1H), 4.77-4.90 (m, 3H), 6.65 (m, 2H), 7.45 (m, 5H). Data: 1H NMR Dimethoxy-N-benzoyl-PZQ (MW54-3) (T=323K).pdf
13C NMR (CDCl3, 50.3 MHz): delta = 28.2, 39.0, 46.3 (br), 51.1 (br), 54.6 (br), 55.8, 56.1, 108.1, 111.7, 124.2 (br), 127.1 (br), 127.3 (2C), 128.6 (2C), 130.6, 134.2 (br), 148.0, 148.3, 164.2, 170.1. Data: 13C _NMR MW54-3.pdf, Data: 13C _NMR MW54-3 spreaded (lb 1).pdf
IR: nu = 2932, 2907, 1637, 1514, 1413, 1252, 1224, 1069, 1028, 851, 789, 703, 554. Data: IR MW54-3.pdf
MS (ESI, +): m/z (%): 755 [2M + Na]+ (100), 389 [M + Na] (34).
HRMS (ESI, +) Calcd. for [C21H22N2NaO4]+: 389.14718, found: 389.14737.
C21H22N2O4 (366.4 g/mol).

Related reactions:
Acid-catalyzed Pictet-Spengler reaction with binaphthalenedisulfonic acid (MW56-1 to MW56-4)
Acid-catalyzed Pictet-Spengler reaction with methanesulfonic acid (MW56-5 to MW56-8)

References:
[1] Polycyclic Compounds by Ugi−Pictet−Spengler Sequence, W. Wang†, S. Ollio†, E. Herdtweck and A. Doemling, J. Org. Chem. 2011, 76 (2), pp 637–644. (DOI: 10.1021/jo102058s)
scheme.png
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22nd February 2011 @ 09:28
Acid-mediated cyclization of the N-benzoyl-protected Ugi intermediate MW51-1 with methanesulfonic acid

scheme.png


See:
Acid-mediated Pictet-Spengler of the N-benzoyl-Ugi intermediate (MW53-1 to MW53-3)
and related experiments:
Attempts to the Bronstedt-acid catalysed Pictet-Spengler cyclization using BINOL-N-triflyl phosphoramide (MW41)
Cleavage of the dimethoxy acetal of 2-((2,2-dimethoxyethyl)amino)-N-phenethylacetamide hydrochloride MW7(MW42)

Hazard and Risk Assessment:
HRAF MW53.pdf


Start time: 8:10 PM 22/02/2011
End time: 9:00 PM 23/02/2011

MW51-1 (300 mg, 810 µmol, M.W. 370.4 g/mol) was stirred with methanesulfonic acid (1 mL) for 13 h at 60°C.
- work-up: quenched with water, neutralized with Na2CO3, extracted with DCM, dried with Na2SO4, evaporated.
Crude yield: 263 mg (858 mmol, 106%) brown oil [M.W. 306.4 g/mol]

Column (silica gel, ethyl acetate, 100%), Rf 0.45 (ethyl acetate, 100%)
Yield: 186 mg (607 µmol, 75%) pale orange solid

Analytical data:
Rf 0.45 (ethyl acetate, 100%).
m.p. 158-159.5°C.
1H NMR (CDCl3, 200 MHz): 2.73-3.11 (m, 4 H), 4.02-4.11 (m, 1H), 4.40 (br s, 1H), 4.80-5.00 (m, 2H), 5.19 (br s, 1H), 7.23 (br s, 4 H), 7.48 (br s, 5H). rotamers strong signal broadening Data: 1H NMR MW53-4
1H NMR (CDCl3, 200 MHz, T=323K): delta = 2.73-3.17 (m, 4 H), 4.04 (d, J=17.5 Hz, 1H), 4.55 (br d, J=17.5 Hz, 1H), 4.72-4.88 (m, 2H), 4.94 (d, 8.7Hz, 1H)7.14-7.28 (m, 4 H), 7.44-7.47 (m, 5H). Data: 1H NMR N-benzoyl-PZQ (MW53-4) (T=323K).pdf
13C NMR (CDCl3, 50.3 MHz): delta = 28.8, 39.0, 46.4 (b), 51.2 (b), 55.0 (b), 125.4 (b), 127.0, 127.4 (b, 2C), 127.6, 128.8 (2C), 129.5, 130.7, 132.6 (b), 134.3, 135.0, 164.4, 170.3.
Data: 13C NMR MW53-4 N-benzoyl-PZQ.pdf, Data: 13C NMR MW53-4 N-benzoyl-PZQ spread.pdf -> signal broadening due to rotamers, it's difficult to distinguish which of the signal at 127.4 and 127.6 contains to or 1 C (in total 3 C's determined by integration)
IR: nu = 2920, 1612, 1420, 1293, 1247, 758, 717, 656, 555 cm-1. Data: IR MW53-4.pdf
MS (ESI, +): m/z (%): 635 [2M + Na]+ (100), 329 [M + Na] (35).
HRMS (ESI, +) Calcd. for [C19H18N2NaO2]+: 329.12605, found: 329.12588.
C19H18N2O2 (306.4 g/mol).

Related reactions:
Acid-catalyzed Pictet-Spengler reaction with binaphthalenedisulfonic acid (MW56-1 to MW56-4)
Acid-catalyzed Pictet-Spengler reaction with methanesulfonic acid (MW56-5 to MW56-8)
Continuation: Acid-catalyzed Pictet-Spengler reaction with methanesulfonic acid (MW56-9 to MW56-14)

References:
[1] Polycyclic Compounds by Ugi−Pictet−Spengler Sequence, W. Wang†, S. Ollio†, E. Herdtweck and A. Doemling, J. Org. Chem. 2011, 76 (2), pp 637–644. (DOI: 10.1021/jo102058s)
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21st February 2011 @ 08:37
Attempts to the acid-mediated cyclization of the dimethoxy-N-benzoyl-protected Ugi intermediate MW52-1 with methanesulfonic acid

scheme.png


Hazard and Risk Assessment:
HRAF MW53.pdf


Start time: 7:10 PM 21/02/2011
End time: 7:30 PM 21/02/2011

MW54-1:
MW52-1 (36 mg, 83.7 µmol, M.W. 430.5 g/mol) was stirred with methanesulfonic acid (0.5 mL) for 14 h at room temperature.
- work-up: neutralized with Na2CO3, extracted with DCM, dried with Na2SO4, evaporated
Data: 1H NMR MW54-1.pdf

MW54-2:
MW52-1 (30 mg, 69.8 µmol, M.W. 430.5 g/mol) was stirred with formic acid (0.5 mL) for 14 h at room temperature.
- work-up: neutralized with Na2CO3, extracted with DCM, dried with Na2SO4, evaporated
Data: 1H NMR MW54-2.pdf

-> no specific signals in NMR visible

TLC (Rf=0.31; ethyl acetate, 100%; stain: potassium permanganate): same Rf for starting material and product, product stains without heating and more intense.
Stain: ceric ammonium molybdate: product stains more greenish and paler than the starting material.

MW54-1: Product and side product (small amout of product, no starting material, lots of side product)
MW54-2: minor side products (NMR: no starting material visible)
-> reaction with formic acid is more selective

TLC.JPG



Related reactions:
Synthesis of the dimethoxy-N-benzoyl-derivative of PZQ via Pictet-Spengler reaction (MW54-3)
Acid-catalyzed Pictet-Spengler reaction with binaphthalenedisulfonic acid (MW56-1 to MW56-4)
Acid-catalyzed Pictet-Spengler reaction with methanesulfonic acid (MW56-5 to MW56-8)

References:
[1] Polycyclic Compounds by Ugi−Pictet−Spengler Sequence, W. Wang†, S. Ollio†, E. Herdtweck and A. Doemling, J. Org. Chem. 2011, 76 (2), pp 637–644. (DOI: 10.1021/jo102058s)
scheme.png
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17th February 2011 @ 08:19
Attempts to the acid-mediated cyclization of the N-benzoyl-protected Ugi intermediate MW51-1 with methanesulfonic acid

See also:
Attempts to the Bronstedt-acid catalysed Pictet-Spengler cyclization using BINOL-N-triflyl phosphoramide (MW41)
Cleavage of the dimethoxy acetal of 2-((2,2-dimethoxyethyl)amino)-N-phenethylacetamide hydrochloride MW7(MW42)

Reaction Scheme


Hazard and Risk Assessment:
HRAF MW53.pdf


MW53-1:
Start time: 7:30 PM 17/02/2011
End time: 10:10 PM 21/02/2011
MW51-1 (31 mg, 83.8 µmol, M.W. 370.4 g/mol) was stirred with methanesulfonic acid (0.5 mL) for 15 h at room temperature.
- work-up: neutralized with Na2CO3, extracted with DCM, dried with Na2SO4, evaporated
Data: 1H NMR MW53-1.pdf

MW53-2:
Start time: 7:30 PM 17/02/2011
End time: 9:30 PM 21/02/2011
MW51-1 (29 mg, 78.4 µmol, M.W. 370.4 g/mol) was stirred with formic acid (0.5 mL) for 4 days at room temperature.
- work-up: neutralized with Na2CO3, extracted with DCM, dried with Na2SO4, evaporated
Data: 1H NMR MW53-2.pdf

MW53-3:
Start time: 7:15 PM 21/02/2011
End time: 9:30 PM 22/02/2011
MW51-1 (31 mg, 83.8 µmol, M.W. 370.4 g/mol) was stirred with methanesulfonic acid (0.5 mL) for 14 h at 60°C.
- work-up: neutralized with Na2CO3, extracted with DCM, dried with Na2SO4, evaporated
TLC: Rf=0.43 (ethyl acetate, 100%, stain ceric ammonium molybdate)- no starting material
Data: 1H NMR MW53-3.pdf: no specific signals because of rotamers

TLC: (Rf=0.43; ethyl acetate, 100%, stain: potassium permanganate), same Rf for starting material and product, product stains without heating.
- Stain: ceric ammonium molybdate: product doesn't stain.
TLC MW53.JPG


Results:
MW53-1: still starting material, + side products. (after 12 h - no product visible)
MW53-2: colourful reaction, no visible starting material, lots of side product (after 2 d - product and a lot of side product)
MW53-3: look like a clean reaction (product - almost clean reaction)


References:
[1] Polycyclic Compounds by Ugi−Pictet−Spengler Sequence, W. Wang†, S. Ollio†, E. Herdtweck and A. Doemling, J. Org. Chem. 2011, 76 (2), pp 637–644. (DOI: 10.1021/jo102058s)
Linked Posts
Attached Files
15th February 2011 @ 00:09
Synthesis of a electron-rich precursor derivative of PZQ with a N-benzoyl protecting group via the Ugi multi-component reaction

Scheme MW52-1.png


See:
Preparation of the dimethoxy ‘Ugi-intermediate’ via Ugi reaction (MW40)
and related reactions:
Preparation of the N-benzoyl-protected 'Ugi-intermediate' (MW51-1)
Preparation of the Ugi-intermediate via Ugi reaction (MW36-1)
Optimizing conditions for the Ugi reaction (MW36-2 to MW36-5)

Hazard and Risk Assessment:
HRAF MW51.pdf


Start time: 12:00 AM 15/02/2011
End time: 10:00 AM 17/02/2011

To a mixture of paraformaldehyde (94 mg, 3.14 mmol, 1.0 eq., M.W 30.0), 2,2-dimethoxyethylamine (330 mg, 3.14 mmol, 308 µL, 1.0 eq., M.W. 105.1 g/mol, d=0.973 g/mL) and benzoic acid (383 mg, 3.14 mmol, 1.0 eq., M.W. 122.12 g/mol) in methanol (2 mL) was added slowly 2-(3,4-Dimethoxyphenyl)ethyl isocyanide MW37-2 (600 mg, 3.14 mmol, 1.0 eq., M.W. 191.2) and stirred at room temperature for 46 h.
The solvent was evaporated, the residue was dissolved in ethyl acetate and washed subsequently with 0.5 N HCl solution and Na2CO3 solution. The organic layer was dried over MgSO4 and concentrated under reduced presssure.

- Crude yield: 1.35 g (3.12 mmol, 99%) orange oil [M.W. = 430.5 g/mol]
Data: 1H NMR MW52-1 crude.pdf

Column chromatography (silica gel, ethyl acetate:hexane, 1:1; then ethyl acetate, 100%), evaporated under high vac (4 h)
Rf=0.08 (ethyl acetate:hexane, 1:1), Rf=0.35 (ethyl acetate, 100%).
Yield: 1.36 g (3.16 mmol, 101%) pale yellow, highly viscous oil
TLC MW52-1.JPG


Analytical data:
Rf=0.08 (ethyl acetate:hexane, 1:1), Rf=0.35 (ethyl acetate, 100%).
1H NMR (CDCl3, 200 MHz, 300K): 2 rotamers, very broad signals Data: 1H NMR MW52-1.pdf.
1H NMR (CDCl3, 200 MHz, T=328K): δ = 2.78 (t, J=6.9Hz, 2 H), 3.32 (s, 6H), 3.45-3.58 (m, 4H), 3.82 (s, 3H), 3.83 (s, 3H), 4.05 (br s, 2H), 4.56 (br s, 1H), 6.64 (br s, 1H), 6.71-6.81 (m, 3H), 7.34 (m, 5H). Data: 1H NMR MW52-1 (T=528K).pdf
13C NMR (CDCl3, 200 MHz, T=328K): δ = 35.1, 40.7, 50.6-52.6 (br m, 2C), 55.1 (br s, 2C), 55.9 (2C), 102.9, 111.4, 111.9, 120.7, 126.9 (2C), 128.5 (2C), 130.1, 131.3, 135.3, 147.7, 149.1, 168.8, 173.1. Data: 13C NMR MW52-1.pdf
IR (neat): nu = 3311 cm-1, 3000, 2937, 2836, 1631, 1513, 1453, 1260, 1233, 1126, 1074, 1025, 750, 701. Data: IR MW52-1.pdf
MS (ESI, +) m/z (%): 883 [2M + Na]+ (59), 453 [M + Na] (100).
HRMS (ESI (+)) Calcd. for [C23H30N2NaO6]+: 453.19961, found: 453.19974.
C23H30N2O6 (430.5 g/mol).

Results:
Convenient and efficient 2-step synthesis of MW52 via the Ugi-multicomponent reaction. The isolated yield is >95% however due to the high viscosity of the compound traces of solvents remained in the product which leads to a yield higher than 100%.

Following reactions:
Acid-mediated Pictet-Spengler of the dimethoxy-N-benzoyl-Ugi intermediate (MW54-1 to MW54-2)
Synthesis of the dimethoxy-N-benzoyl-derivative of PZQ via Pictet-Spengler reaction (MW54-3)
Acid-catalyzed Pictet-Spengler reaction with binaphthalenedisulfonic acid (MW56-1 to MW56-4)
Acid-catalyzed Pictet-Spengler reaction with methanesulfonic acid (MW56-5 to MW56-8)
Attached Files