All Notebooks | Help | Support | About
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
Scheme MW52-1.png
IR MW52-1.pdf
1H NMR MW52-1 crude.pdf
1H NMR MW52-1.pdf
1H NMR MW52-1 JCAMP-DX.dx
1H NMR MW52-1 (T=528K).pdf
TLC MW52-1.JPG
13C NMR MW52-1.pdf
1H NMR MW52-1 (T=328K).dx
13C NMR MW52-1.dx