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Pictet-Spengler route to Praziquantel
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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

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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)
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Attached Files
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1H NMR MW54-3.pdf
IR MW54-3.pdf
13C _NMR MW54-3.pdf
13C _NMR MW54-3 spreaded (lb 1).pdf
1H NMR Dimethoxy-N-benzoyl-PZQ (MW54-3) (T=323K).pdf
1H NMR Dimethoxy-N-benzoyl-PZQ (MW54-3) (T=323K) JCAMP-DX.dx
13C NMR MW54-3.dx