UGI REACTION, MULTICOMPONENT SYNTHESISSHORT PRESENTATION

MARCH 2012

Dr. ANTHONY MELVIN CRASTOPRINCIPAL SCIENTIST

This is a vast topic and a short overview is givenand

in no way complete justice can be done for this

MECHANISM

DRUGS

VARIATIONS

Ugi-Diels-Alder reaction

Ugi-Smiles reaction

Ugi-Buchwald-Hartwig reaction

Ugi-Heck reaction

REVIEWS

SYNTHESIS

Ugi Reaction; N-allyl-N-(2-(cyclohexylamino)-2-oxo-1-phenylethyl)-3-nitropropanamide

Chemicals UsedBenzaldehyde (Acros Organics)Allylamine (Merck)Cyclohexyl isocyanide (Merck)3-Nitropropionic acid (Sigma)MeOHProcedureA solution of  benzaldehyde (1.70 mmol, 0.172 mL), allylamine (1.70 mmol, 0.128 mL), cyclohexyl isocyanide (1.70 mmol, 0.211 mL) and 3-nitropropionic acid (1.70 mmol, 0.202 g) in 10 mL MeOH was stirred at room temperature under nitrogen atmosphere. After 28 h, the solution was concentrated under reduced pressure to leave a pale yellow solid. The residue was washed with cold Et2O (3 x 20 mL) to give pure title compound as a white solid (475 mg, 75% yield, mp 190-192 °C, Rf= 0.44 (ethyl acetate-hexane; 1 : 1).  1H and 13C NMR spectra showed title compound is a mixture of two rotamers in an approximately 1:4.5 ratio.

Data IR-ATR: 3258, 3084, 2926, 2855, 1638, 1629, 1547 cm-1.

1H NMR (400 MHz, DMSO-d6): (both rotamers) ppm = 8.30 (0.18H, d, NH, J= 7.71 Hz), 8.21 (0.82H, d, NH, J= 7.71 Hz), 7.40-7.28 (3H, m, aromatic CH), 7.22 (2H, d, aromatic CH, J= 7.08 Hz), 6.12 (0.82H, s, CH-Ar), 5.65 (0.18H, s, CH-Ar), 5.45-5.37 (1H, m, CH2=CH), 5.02 (1H, appear d, CH2=CH, J=17.39 Hz), 4.95 (1H, dd, CH2=CH, J= 1.12, 10.40 Hz), 4.75-4.72 (2H, m, CH2NO2), 4.04 (2H, m, CH2=CHCH2), 3.60-3.55 (1H, m, CHNH), 3.05 (2H, t, CH2CH2NO2, J=5.23Hz), 1.75-1.62 (4H, m, cyclohexyl CH2), 1.55-1.52 (1H, m, cyclohexyl CH2), 1.30-1.04 (5H, m, cyclohexyl CH2).13C NMR (100 MHz, DMSO-d6): (both rotamers) ppm = 170.17, 169.24, 167.95, 167.34, 136.47, 136.13, 134.83, 134.27, 128.80, 128.47, 128.41, 128.02, 127.84, 115.85, 115.23, 70.53, 62.28, 59.66, 47.75, 47.65, 47.31, 46.87, 32.17, 32.05, 30.03, 25.11, 24.53, 24.43.

  Lead Reference 1. Ugi, I.; Meyr, R. Angew. Chem., 1958, 70, 702.

2. Ugi, I.; Meyr, R. Fetzer, U. Angew. Chem., 1959, 71, 373. 3. Ugi, I.; Offermann, K. Angew. Chem. Int. Ed. Engl., 1963, 2, 624.4. Akritopoulou-Zanze, I., Gracias, V., Moore, J. D., Djuric, S. W. Tetrahedron Lett., 2004, 45, 3421.

1-cyclohexenyl isocyanide (47 mg, 50.2 µL,0.44 mmol) was added to a solution ofpropionic acid (33 mg, 32.9 µL,0.44 mmol), aniline (41 mg, 40.1 µL, 0.44 mmol), 4-phenylethylpiperidone (90 mg, 0.44 mmol) in MeOH (2.2 mL) at room temperature and the solutionwas heated at 55 C and stirred for 24 h. The solvent was removed underreduced pressure, and the residue was dissolved in EtOAc (5 mL). The organic solution was washed with sat aq NaHCO3 (2 2.5 mL) and brine (2.5 mL) and dried (MgSO4), and the solvent was removed under reduced pressure. The crude product was purified either via HPLC/MS preparative with gradient starting from 10% MeOH / 90% H2O / 0.1% ammonia reaching 100% MeOH / 0.1%ammonia. The product was obtained in 82% yield (165 mg).

  Reference: Tetrahedron Letters 

Volume 51, Issue 22, 2 June 2010, Pages 2983-2985

amcrasto@gmail.comDR ANTHONY CRASTO

chemistry sites https://sites.google.com/site/anthonycrastoorganicchemistry/sites---my-own-on-the-net

THANKS AND REGARD'SDR ANTHONY MELVIN CRASTO Ph.Damcrasto@gmail.com

MOBILE-+91 9323115463 GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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