M. D’hooghe et al. / Tetrahedron 64 (2008) 1064–1070
1069
3.1.4.1. 1-Benzyl-5-methoxypyrrolidin-2-one 14a.
Yield 46%. Yellow oil. Rf¼0.31 (hexane/EtOAc 7:3). H
Acknowledgements
1
NMR (300 MHz, CDCl3): d 1.94–2.16 (2H, m, CH2CH);
2.37 (1H, dꢁdꢁd, Jgem¼17.3, 9.6, 3.6 Hz, (HCH)C]O);
2.48–2.65 (1H, m, (HCH)C]O); 3.21 (3H, s, OCH3); 4.01
and 4.95 (2H, 2ꢁd, J¼14.6 Hz, (HCH)N); 4.73 (1H, dꢁd,
J¼6.2, 1.3 Hz, CHO); 7.25–7.36 (5H, m, CHarom). 13C
NMR (75 MHz): d 23.70 (CH2CH); 29.01 (CH2C]O);
43.77 (CH2N); 52.90 (OCH3); 88.97 (CHO); 127.57
(HCarom,para); 128.40, 128.63 (2ꢁHCorthoHCmeta); 136.44
(Carom,quat); 174.84 (C]O). IR (NaCl, cmꢂ1):
nC]O¼1750, 1694. MS (70 eV): m/z (%): 206 (M++1,
100). Anal. Calcd for C12H15NO2: C 70.22, H 7.37, N
6.82. Found: C 70.40, H 7.59, N 6.71.
The authors are indebted to the ‘Fund for Scientific Re-
search—Flanders (Belgium)’ (F.W.O.-Vlaanderen) and to
Ghent University (GOA) for financial support.
References and notes
€
1. Brauner-Osborne, H.; Egebjerg, J.; Nielsen, E. Ø.; Madsen, U.;
Krogsgaard-Larsen, P. J. Med. Chem. 2000, 43, 2609.
2. Selected examples from the last five years: (a) Moonen, K.; Van
ꢀ
Meenen, E.; Verwee, A.; Stevens, C. V. Angew. Chem., Int. Ed.
2005, 44, 7407; (b) Lu, I. L.; Lee, S. J.; Tsu, H.; Wu, S. Y.; Kao,
K. H.; Chien, C. H.; Chang, Y. Y.; Chen, Y. S.; Cheng, J. H.;
Chang, C. N.; Chen, T. W.; Chang, S. P.; Chen, X.; Jiaang,
W. T. Bioorg. Med. Chem. Lett. 2005, 15, 3271; (c) Diez, D.;
Garcia, P.; Marcos, I. S.; Garrido, N. M.; Basabe, P.;
Broughton, H. B.; Urones, J. G. Tetrahedron 2005, 61, 699;
(d) Brimble, M. A.; Trotter, N. S.; Harris, P. W. R.; Sieg, F.
Bioorg. Med. Chem. 2005, 13, 519; (e) Greenfield, A. A.;
Butera, J. A. Synth. Commun. 2004, 34, 3939; (f) Battistini,
L.; Curti, C.; Zanardi, F.; Rassu, G.; Auzzas, L.; Casiraghi,
G. J. Org. Chem. 2004, 69, 2611; (g) Conti, D.; Rodriquez,
M.; Sega, A.; Taddei, M. Tetrahedron Lett. 2003, 44, 5327;
(h) Conti, P.; De Amici, M.; Roda, G.; Vistoli, G.; Stensbøl,
3.1.4.2. 1-(4-Methylbenzyl)-5-methoxypyrrolidin-2-
one 14b. Yield 62%. Yellow oil. Rf¼0.20 (hexane/EtOAc
1
3:2). H NMR (300 MHz, CDCl3): d 1.92–2.13 (2H, m,
CH2CH); 2.33 (CH3C); 2.38 (1H, dꢁdꢁd, Jgem¼17.3, 9.4,
3.6 Hz, (HCH)C]O); 2.57 (1H, dꢁdꢁd, Jgem¼17.3, 8.9,
8.9 Hz, (HCH)C]O); 3.22 (3H, s, OCH3); 3.96 and 4.93
(2H, 2ꢁd, J¼14.6 Hz, (HCH)N); 4.72 (1H, dꢁd, J¼6.1,
1.7 Hz, CH); 7.17–7.29 (4H, m, CHarom). 13C NMR
(75 MHz, ref¼CDCl3): d 21.20 (CH3C); 23.80 (CH2CH);
29.16 (CH2C]O); 43.58 (CH2N); 52.97 (OCH3); 88.98
(OCH); 128.55–129.41 (HCarom); 133.48 (CH3C); 137.36
(NCH2Carom,quat); 174.83 (C]O). IR (NaCl, cmꢂ1):
nC]O¼1758. MS (70 eV): m/z (%): 220 (M++1, 100).
Anal. Calcd for C13H17NO2: C 71.21, H 7.81, N 6.39. Found:
C 71.36, H 8.03, N 6.27.
€
T. B.; Brauner-Osborne, H.; Madsen, U.; Toma, L.; De
Micheli, C. Tetrahedron 2003, 59, 1443; (i) Bunch, L.;
Liljefors, T.; Greenwood, J. R.; Frydenvang, K.; Brauner-
€
Osborne, H.; Krogsgaard-Larsen, P.; Madsen, U. J. Org.
Chem. 2003, 68, 1489; (j) de Dios, A.; Prieto, L.; Martin,
J. A.; Rubio, A.; Ezquerra, J.; Tebbe, M.; de Uralde, B. L.;
Martin, J.; Sanchez, A.; LeTourneau, D. L.; McGee, J. E.;
Boylan, C.; Parr, T. R.; Smith, M. C. J. Med. Chem. 2002,
45, 4559; (k) Li, C. Adv. Drug Delivery Rev. 2002, 54, 695.
3. (a) Groger, H. Chem. Rev. 2003, 103, 2795; (b) Enders, D.;
Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359; (c) Winkler,
M.; Martinkova, L.; Knall, A. C.; Krahulec, S.; Klempier, N.
Tetrahedron 2005, 61, 4249; (d) Preiml, M.; Honig, H.;
Klempier, N. J. Mol. Catal. B: Enzym. 2004, 29, 115.
3.1.4.3. 1-(4-Chlorobenzyl)-5-methoxypyrrolidin-2-
one 14c. Yield 65%. Yellow oil. Rf¼0.38 (hexane/EtOAc
1
2:3). H NMR (300 MHz, CDCl3): d 1.93–2.15 (2H, m,
CH2CH); 2.36 (1H, dꢁdꢁd, J¼17.4, 9.6, 3.6 Hz,
(HCH)C]O); 2.55 (1H, dꢁdꢁd, J¼17.4, 8.8, 8.8 Hz,
(HCH)C]O); 3.18 (3H, s, OCH3); 4.00 and 4.83 (2H,
2ꢁd, J¼14.7 Hz, (HCH)N); 4.70 (1H, dꢁd, J¼6.1, 1.7 Hz,
CHO); 7.17–7.29 (4H, m, CHarom). 13C NMR (75 MHz,
ref¼CDCl3):
d 23.78 (CH2CH); 29.03 (CH2C]O);
43.37 (CH2N); 52.94 (CH3); 89.14 (CH); 128.90–
129.91 (HCarom); 133.56–135.15 (2ꢁCarom,quat); 174.95
(C]O). IR (NaCl, cmꢂ1): nC]O¼1694. MS (70 eV):
m/z (%): 240/2 (M++1, 100). Anal. Calcd for C12H14ClNO2:
C 60.13, H 5.89, N 5.84. Found: C 60.22, H 6.11,
N 5.90.
4. (a) Juaristi, E.; Soloshonok, V. Enantioselective Synthesis of
b-Amino Acids, 2nd ed.; John Wiley & Sons: Hoboken, 2005;
(b) Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1; (c)
ꢀ
Juaristi, E.; Lopez-Ruiz, H. Curr. Med. Chem. 1999, 6, 983;
(d) Cole, D. C. Tetrahedron 1994, 50, 9517; (e) Fulop, F.
Chem. Rev. 2001, 101, 2181; (f) Trabocchi, A.; Guarna, F.;
Guarna, A. Curr. Org. Chem. 2005, 9, 1127.
€ €
3.1.4.4. 1-(4-Methoxybenzyl)-5-methoxypyrrolidin-2-
one 14d. Yield 48%. Yellow oil. Rf¼0.20 (hexane/EtOAc
5. Shimizu, M.; Kamiya, M.; Hachiya, I. Chem. Lett. 2005, 34,
1456.
1
7:3). H NMR (300 MHz, CDCl3): d 1.92–2.13 (2H, m,
6. Selected examples: (a) Cheng, M.; Li, Q.; Lin, B.; Sha, Y.; Ren,
J.; He, Y.; Wang, Q.; Hua, H.; Ruud, K. Tetrahedron:
Asymmetry 2006, 17, 179; (b) Akue-Gedu, R.; Henichart, J.-
P.; Couturier, D.; Rigo, B. Tetrahedron Lett. 2004, 45, 9197;
(c) Godet, T.; Bonvin, Y.; Vincent, G.; Merle, D.; Thozet, A.;
Ciufolini, M. A. Org. Lett. 2004, 6, 3281; (d) Aoki, S.; Cao,
L.; Matsui, K.; Rachmat, R.; Akiyama, S.-i.; Kobayashi, M.
Tetrahedron 2004, 60, 7053; (e) Elliott, M. C.; Long, M. S.
Org. Biomol. Chem. 2004, 2, 2003; (f) Belokon, Y. N.;
Bhave, D.; D’Addario, D.; Groaz, E.; North, M.; Tagliazucca,
V. Tetrahedron 2004, 60, 1849; (g) Bourry, A.; Akue-Gedu,
R.; Rigo, B.; Henichart, J.-P.; Sanz, G.; Couturier, D.
J. Heterocycl. Chem. 2003, 40, 989; (h) Edwards, C. W.;
Shipton, M. R.; Alcock, N. W.; Clase, H.; Wills, M.
CH2CH); 2.36 (1H, dꢁdꢁd, J¼17.3, 9.6, 3.7 Hz,
(HCH)C]O); 2.48–2.60 (1H, m, (HCH)C]O); 3.21 (3H,
s, CHOCH3); 3.80 (3H, s, CH3OCarom); 3.95 and 4.90 (2H,
2ꢁd, J¼14.2 Hz, (HCH)N); 4.72 (1H, dꢁd, J¼6.3, 1.7 Hz,
CHO); 6.80–6.90 and 7.08–7.31 (4H, 2ꢁm, CHarom). 13C
NMR (75 MHz, ref¼CDCl3): d 23.75 (CH2CH); 29.23
(CH2C]O); 43.31 (CH2N); 52.87 (CHOCH3); 55.36
(CH3OCarom,quat); 88.92 (CHO); 114.09 (2ꢁMeOHCortho);
129.93 (2ꢁMeOHCmeta); 134.98 (NCH2Carom,quat); 159.15
(CH3OCarom,quat); 174.80 (C]O). IR (NaCl, cmꢂ1):
nC]O¼1748, 1696. MS (70 eV): m/z (%): 236 (M++1,
100). Anal. Calcd for C13H17NO3: C 66.36, H 7.28, N
5.95. Found: C 66.52, H 7.39, N 6.10.