´
A.L.F. de Arriba et al. / Tetrahedron 65 (2009) 4841–4845
4844
4.5. (S)-N-(3,5-Bis(methoxycarbonyl)phenyl)pyrrolidine-2-
carboxamide (7)
dissolved in toluene (5 mL) and allowed to react at 40 ꢀC and
20 mmHg for 2 h. Additional toluene portions were added under
argon atmosphere when the reaction mixture turned viscous.
Diethyl ether (20 mL) was then added and the mixture was cooled
to ꢁ80 ꢀC. The precipitate of the product was filtered under argon
(crystals melted before reaching room temperature and decom-
posed in the presence of oxygen) and dried under vacuum
25
White solid, yield 76%; mp: 130–131 ꢀC; [
EtOH); 1H NMR:
(m, 2H), 3.85–3.96 (m, 1H), 3.94 (s, 6H), 8.40 (s, 1H), 8.46 (s,
a
]
D
ꢁ30.18 (c 1.12,
d
1.73–1.80 (m, 2H), 1.90–2.30 (m, 2H), 2.90–3.10
2H) ppm; IR (n
): 1462, 1586, 1729, 2854, 2924 cmꢁ1; ESIHRMS calcd
for C15H19N2O5 [MþH]þ: 307.1288, found: 307.1284.
(0.1 mmHg, 100 ꢀC, 3 h) to obtain the enamine 14 (600 mg, 65%
25
yield). [
a
]
ꢁ124 (c 0.62, CHCl3); 1H NMR:
d 1.20 (s, 3H, H-9), 2.74–
D
4.6. (S)-N-Methyl-N-phenyl-pyrrolidine-2-carboxamide (8)
1.58 (m, 12H), 3.20 (q, J¼9.6 Hz, 1H, H-10), 3.58 (t, J¼9 Hz, 1H, H-
10), 4.07 (dd, J1¼9 Hz, J2¼3 Hz, 1H, H-13), 5.05 (s, 1H, H-5), 5.34 (t,
J¼4.8 Hz, 1H, H-4), 7.10 (t, J¼8 Hz, 1H, H-18), 7.29 (t, J¼8 Hz, 2H, H-
17), 7.48 (d, J¼8 Hz, 2H, H-16), 8.16 (s, 1H, NH) ppm; 13C NMR:
25
White solid, yield 83%; mp: 96–98 ꢀC; [
CHCl3); 1H NMR:
2H), 3.20 (s, 3H), 3.46–3.60 (m, 1H), 7.19 (dd, J1¼6 Hz, J2¼1.4 Hz,
2H), 7.35–7.43 (m, 3H) ppm; 13C NMR:
26.9, 31.8, 38.0, 48.0, 58.8,
a
]
D
ꢁ37.80 (c 1.29,
d
1.52–1.68 (m, 2H), 2.67 (m, 2H), 2.80–3.15 (m,
d
22.2 (C-9), 23.9 (C-3, C-11), 28.9 (C-12), 31.3 (C-8), 35.7 (C-2),
d
44.8 (C-8a), 49.1 (C-10), 63.6 (C-13), 99.9 (C-5), 115.6 (C-4), 119.8
(C-18), 124.4 (C-17), 128.9 (C-16), 137.3 (C-4a), 139.5 (C-15), 142.3
127.9 (ꢂ2), 128.3, 129.9 (ꢂ2), 143.3, 174.6 ppm; ESIHRMS calcd for
C12H17N2O [MþH]þ: 205.1335, found: 205.1323.
(C-6), 172.1 (C-14), 215.4 (C-1); IR (n ;
): 694, 1716, 2923, 3285 cmꢁ1
ESIHRMS calcd for C22H27N2O2 [MþH]þ: 351.2067, found:
4.7. Preparation of
L
-proline-n-butyl ester (9)
351.2054.
L-Proline (5 g, 43.4 mmol), thionyl chloride (5 mL, 68 mmol),
Acknowledgements
and n-butanol (50 mL) were refluxed together for 2 h. The solvent
was removed under reduced pressure and the crude residue was
extracted with ethyl acetate (50 mL) and added to aqueous sodium
carbonate (10% w/v, 100 mL). The organic layer was dried over
We wish to thank Prof. Francisco Bermejo for fruitful discus-
sions, Anna Lithgow for the 400 MHz spectra, and the Spanish
´
´
´
Direccion General de Investigacion, Ciencia y Tecnologıa (DGICYT)
Na2SO4, and the organic solvent was evaporated to dryness to af-
(CTQ-2005-074007BQU).
25
ford butyl ester 9 as an oily compound (85% yield). [
a
]
ꢁ37.86 (c
D
1.38, CHCl3); 1H NMR:
d
0.90 (t, J¼7.2 Hz, 3H), 1.29–1.40 (m, 2H),
Supplementary data
1.56–1.89 (m, 5H), 2.03–2.20 (m, 1H), 2.81–2.92 (m, 1H), 3.02–3.11
1H NMR, 13C NMR, 2D NMR (COSY, HMQC, HMBC), and HRMS
spectra of enamine 14 are provided. HRMS of prolinamides 6–8 and
butyl ester 9 are also included. Supplementary data associated with
this article can be found in the online version, at doi:10.1016/
(m, 1H), 3.71 (dd, J1¼8.8 Hz, J2¼5.8 Hz, 1H), 4.09 (t, J¼6.7 Hz,
2H) ppm; 13C NMR:
d 13.9, 19.3, 25.7, 30.5, 30.9, 47.3, 60.0, 64.9,
175.8 ppm; IR (n
): 1469, 1677, 1742, 2858, 2917 cmꢁ1; ESIHRMS
calcd for C9H18NO2 [MþH]þ: 172.1332, found: 172.1326.
4.8. Preparation of imidazolidinone 11
References and notes
2-Methyl-2-(3-oxobutyl)-cyclopentane-1,3-dione (224 mg, 1.23
mmol) was dissolved in 0.4 mL of CDCl3 and mixed with 393 mg
(1.20 mmol) of the prolinamide catalyst 6. The reaction mixture was
transferred to an NMR tube and allowed to react at 0 ꢀC. After 2 h,
the 1H NMR spectrum recorded displayed the presence of the imid-
azolidinone 11 in 76% yield, according to the integration of the
1. (a) Hajos, Z. G.; Parrish, D. R. German Patent DE 2102623, 1971; (b) Eder, U.;
Sauer, G.; Wiechert, R. German Patent DE 2014757, 1971; (c) Eder, U.; Sauer, G.;
Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10, 496.
2. (a) Nising, C. F.; Braese, S. Angew. Chem., Int. Ed. 2008, 47, 9389; (b) Ken-
nedy, J. W. J.; Vietrich, S.; Weinmann, H.; Brittain, D. E. A. J. Org. Chem.
2008, 73, 5151; (c) Katona, B. W.; Rath, N. P.; Anant, S.; Stenson, W. F.;
Covey, D. F. J. Org. Chem. 2007, 73, 9298; (d) Jastrzebska, I.; Scaglione, J. B.;
Dekoster, N. P.; Rath, N. P.; Covey, D. F. J. Org. Chem. 2007, 73, 4837; (e)
Chochrek, P.; Wicha, J. Org. Lett. 2006, 8, 2551; (f) Buchschacher, P.; Furst,
A.; Gutzwiller, J. Organic Syntheses; Wiley & Sons: New York, NY, 1990; Vol.
VII, p 368.
NMR signals. 1H NMR:
(m, 2H, H-9), 4.10 (dd, 1H, H-12), 7.43 (s, 2H, H-15), 8.06 (s, 1H, H-
17) ppm; 13C NMR:
19.0 (C-8), 24.9 (C-7), 25.4 (C-10), 28.9 (C-6),
d 0.95 (s, 3H, H-8), 1.50–2.50 (m, 14H), 3.10
d
29.2 (C-3), 30.6 (C-2), 33.4 (C-11), 42.8 (C-4), 47.1 (C-9), 52.3 (C-7a),
63.2 (C-12), 77.9 (C-3a), 82.5 (C-5), 122.0 (C-17), 122.7 (C-18, q,
J¼275 Hz), 129.8 (C-15), 132.8 (C-16, q, J¼35 Hz), 137.2 (C-14), 176.3
(C-13), 217.8 (C-1); ESI-MS m/z 491.3 [MþH]þ.
3. (a) Ramachary, D. B.; Kishor, M. J. Org. Chem. 2007, 72, 5056; (b) Davies, S. G.;
Russell, A. J.; Sheppard, R. L.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem.
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4.9. (S)-N-Phenyl-pyrrolidine-2-carboxamide (15)
Freshly distilled aniline (11.8 mL, 129.4 mmol) was dissolved in
dry THF (50 mL) under argon atmosphere and in an ice–salt bath.
Compound 3 (11 g, 64.7 mmol) was added in small portions and the
progress of the reaction was monitored by TLC. Once the reaction
was finished, it was poured into 100 mL of water, Na2CO3 (20 g,
188 mmol) was added, and stirred. Steam distillation and cooling
afforded, after filtration, the pure compound 15 in 81% yield as
a white solid. Prolinamide 15 is a known compound and its physical
and spectroscopic properties are consistent with literature.7j
´
L.; Hua, M.-Q.; Ma, J.-A. Synlett 2008, 1255; (d) Guillena, G.; Najera, C.;
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4.10. Preparation of enamine 14
8. (a) List, B.; Hoang, L.; Martin, H. J. PNAS 2004, 101, 5839; (b) Zotova, N.; Franzke,
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2-Methyl-2-(3-oxobutyl)-cyclohexane-1,3-dione (530 mg, 2.7
´
Gryko, D.; Lipinski, R. Eur. J. Org. Chem. 2006, 3864; (d) Isart, C.; Bures, J.; Vi-
mmol) and aniline prolinamide 15 (513 mg, 2.7 mmol) were
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