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22nd February 2011 @ 09:28
Acid-mediated cyclization of the N-benzoyl-protected Ugi intermediate MW51-1 with methanesulfonic acid

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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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Attached Files
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1H NMR MW53-4
13C NMR MW53-4 N-benzoyl-PZQ.pdf
13C NMR MW53-4 N-benzoyl-PZQ spread.pdf
IR MW53-4.pdf
1H NMR N-benzoyl-PZQ (MW53-4) (T=323K).pdf
1H NMR N-benzoyl-PZQ (MW53-4) (T=323K) JCAMP-DX.dx