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therein.
11. Rosen, T.; Chu, D. T. W.; Lico, I. M.; Fernades, P. B.;
Shen, L.; Borodkin, S.; Pernet, A. G. J. Med. Chem.
1988, 31, 1586.
25. Myers, M. R.; Maguire, M. P.; Spada, A. P.; Ewing, W.
R.; Pauls, H. W.; Choi-Sledeski, Y. M. WO 0023,447;
Chem. Abstr. 2000, 132, 29976s.
4-Amino 1-benzylpyrrolidin-2-one 6:
From hydrazide 8: To a solution of hydrazide 8 (13 g,
55.7 mmol) in water (100 ml) was added successively
trifluoroacetic acid (13 ml, 167.2 mmol) and NaNO2 (5.8
g, 83.6 mmol) at 0°C. The mixture was gradually heated
at 80°C until gas evolution ceased. Aqueous sodium
hydroxide (30 ml, 6N) was then added to the mixture.
The aqueous layer was extracted with CH2Cl2 (2×150
ml), then EtOAc (3×150 ml). The combined organic
layers were dried over Na2SO4 and concentrated under
reduced pressure to afford 6 as a yellow oil (7.4 g, 70 %);
1H NMR (CDCl3, 400 MHz): l 1.43 (br s, NH2), 2.21
(dd, J=4.7, 16.9 Hz, 1H), 2.73 (dd, J=7.5, 16.9 Hz, 1H),
2.94 (dd, J=4.0, 10.0 Hz, 1H), 3.47 (dd, J=6.6, 10.0 Hz,
1H), 3.66 (m, 1H), 4.46 (s, 2H), 7.24–7.53 (m, 5H); 13C
NMR (CDCl3, 62.5 MHz): l 40.3, 44.0, 45.6, 54.9, 127.8,
128.1, 135.6, 172.7; IR (NaCl): 3428, 1684, 1442, 1210,
1134 cm−1; MS m/z (rel. int.): 190 (12), 120 (28), 91 (41),
59 (28), 58 (24), 45 (100). Anal. calcd for C11H14N2O: C,
69.45; H, 7.42; N, 14.72. Found: C, 69.11; H, 7.50; N,
15.06%.
12. de Costa, B. R.; Dominguez, C.; He, X.; Williams, W.;
Radesca, L.; Bowen, W. J. Med. Chem. 1992, 35, 4334.
13. Crider, A. M.; Lamey, R.; Floss, H. G.; Cassady, J. M.;
Bradner, W. J. J. Med. Chem. 1980, 23, 848.
14. Moragues, J.; Prieto, J.; Spickett, R. G. W.; Vega, A. J.
Chem. Soc., Perkin Trans. 1 1976, 938.
15. Hojo, T.; Yokoyama, T.; Nakazono, K.; Okada, M.
JP90/02218664; Chem. Abstr. 1991, 114, 81579t.
16. (a) Wallis, E. S.; Lane, J. F. Org. React. 1946, 3, 267; (b)
Hirose, T.; Minamida, A.; Okada, H.; Nakano, J.; Mat-
sumoto, J. JP88/51370; Chem. Abstr. 1988, 109, 92775b.
17. Smith, P. A. Org. React. 1946, 3, 337.
18. Rogers, D. H.; Saunders, J.; John, P. DE 19,955,794;
From amide 5: PhI(OAc)2 (982 mg, 3.05 mmol) was
added to a solution of amide 5 (500 mg, 2.29 mmol) in
H2O (20 ml) and MeCN (20 ml). The mixture was stirred
for 1 h at rt before adding H2O (10 ml), then HCl (2 ml,
37%). The aqueous layer was washed with CH2Cl2 and
water was removed under vacuum to give the hydrochlo-
Chem. Abstr. 2000, 133, 4595k.
1-Benzyl-5-oxo-pyrrolidine-3-carboxamide 5: A mixture
of ester 3 (10 g, 43 mmol) was stirred overnight with
ammonium hydroxide (46 ml, 28%) at rt. Filtration
yielded amide 5 as a white solid (6.8 g, 72%); mp 166°C
1
1
(MeOH/Et2O); H NMR (CDCl3, 400 MHz): l 2.69 (dd,
ride of 6 (407 mg, 78 %); mp 200°C; H NMR (D2O, 400
J=9.7, 16.9 Hz, 1H), 2.79 (dd, J=8.0, 16.9 Hz, 1H), 3.09
(qt, J=8.8 Hz, 1H), 3.43 (dd, J=9.9, 8.8 Hz, 1H), 3.54
(dd, J=7.0, 9.9 Hz, 1H), 4.38 (d, J=14.7 Hz, 1H), 4.56
(d, J=14.7 Hz, 1H), 5.6 (br s, NH2), 7.24–7.37 (m, 5H);
13C NMR (CDCl3, 62.5 MHz): l 35.2, 37.3, 47.0, 49.3,
128.2, 128.6, 129.2, 136.3, 172.7, 174.4; IR (KBr): 3340,
3168, 1676, 1636, 1444, 1292 cm−1; MS m/z (rel. int.): 218
(18), 190 (18), 146 (36), 118 (55), 106 (30), 91 (100), 86
(98). Anal. calcd for C12H14N2O2: C, 66.04; H, 6.47; N,
12.84. Found: C, 66.48; H, 6.54; N, 12.72%.
MHz): l 2.55 (dd, J=3.4, 18.1 Hz, 1H), 2.98 (dd, J=
18.1, 8.6 Hz, 1H), 3.38 (dd, J=3.0, 12.0 Hz, 1H), 3.74
(dd, J=12.0, 7.4 Hz, 1H), 4.03 (m, 1H), 4.32 (d, J=15
Hz, 1H), 4.52 (d, J=15 Hz, 1H), 7.23–7.43 (m, 5H); 13C
NMR (D2O, 62.5 MHz): l 36.0, 43.8, 46.8, 51.3, 128.6,
129.4, 135.4, 173.8; IR (KBr): 3046, 2938, 2878, 1680
cm−1
.
26. 1-Benzyl-pyrrolidin-3-ylamine 1: A solution of amide 6
(11 g, 57.8 mmol) in dry THF (330 ml) was added slowly
at rt to a suspension of LiAlH4 (4.4 g, 115.6 mmol) in dry
THF (330 ml). The mixture was refluxed for 3 h under
N2, cooled to rt, and carefully treated with water (4.4 ml),
aqueous sodium hydroxide (15%, 4.4 ml) and water (13.2
ml). The mixture was dried over Na2SO4 and concen-
trated under reduced pressure to afford 1 as a yellow oil
19. Suppliers: Aldrich (3, 98%), Acros (4a, 98%).
20. Huang, X.; Seid, M.; Keillor, J. W. J. Org. Chem. 1997,
62, 7495.
21. Baumgarten, H. E.; Smith, H. L.; Staklis, A. J. Org.
Chem. 1975, 40, 3554.
1
22. For example, see: (a) PhIO–HCOOH: Radhakrishna, A.
S.; Rao, C. D.; Varma, R. K.; Sing, B. B.; Bhatnagar, S.
P. Synthesis 1983, 538. (b) PhI(OTs)OH: Lazbin, I. M.;
Koser, G. F. J. Org. Chem. 1986, 51, 2669.
(8 g, 80%). H NMR (CDCl3, 400 MHz) was identical to
the one previously described.11 The monohydrochloride
of 1 was recrystallized from iPrOH/(iPr)2O. 1·HCl: 1H
NMR (D2O, 400 MHz): l 1.72 (m, 1H), 2.22 (m, 1H),