A. Zanobini, M. Gensini, J. Magull, D. Vidovic, S. I. Kozhushkov, A. Brandi, A. de Meijere
FULL PAPER
(m, 5 H, Ar-H) ppm. 13C NMR (50.3 MHz): δ ϭ 7.3 (CH2), 7.7
the β-lactam 7a (990 mg, 78%) as a yellow oil. IR (film): ν˜ ϭ 3065
(CH2), 8.2 (CH2), 11.2 (CH2), 62.5 (CH), 66.6 (C), 128.0 (CH), cmϪ1, 3029, 3003, 2953, 2849, 1756, 1729, 1455, 1436. 1H NMR
128.6 (2 CH), 129.2 (2 CH), 135.0 (C), three carbon atom signals
were not detectable at this temperature. 13C NMR (75.5 MHz,
(250 MHz): δ ϭ 0.84Ϫ0.92 (m, 1 H, cPrϪH), 1.06Ϫ1.16 (m, 1 H,
cPrϪH), 1.18Ϫ1.29 (m, 2 H, cPrϪH), 3.71 (s, 3 H, OCH3), 4.02 (s,
C2D2Cl4, 100 °C): δ ϭ 7.0 (CH2), 7.4 (CH2), 7.7 (CH2), 10.5 (CH2), 1 H, CH), 4.24 (d, J ϭ 15.0 Hz, 1 H, CH2), 4.91 (d, J ϭ 15.0 Hz,
30.6 (C), 60.8 (CH2), 62.5 (CH), 66.2 (C), 116.1 (C), 127.6 (CH),
1 H, CH2), 7.25Ϫ7.39 (m, 5 H, Ar-H) ppm. 13C NMR (62.9 MHz):
128.3 (2 CH), 128.8 (2 CH), 135.3 (C) ppm. MS (EI): m/z (%) ϭ δ ϭ 6.5 (CH2), 8.0 (CH2), 37.2 (C), 45.5 (CH2), 52.1 (CH), 57.4
239 (20) [Mϩ Ϫ H], 214 (10), 211 (20), 105 (50), 91 (100). MS (CH3), 127.7 (CH), 128.3 (2 CH), 128.7 (2 CH), 135.2 (C), 170.0
(DCI): m/z (%) ϭ 481 (5) [2 M ϩ Hϩ], 258 (8) [M ϩ NH4ϩ], 241 (C), 170.9 (C) ppm. MS (EI): m/z (%) ϭ 245 (4) [Mϩ], 217 (20),
(100) [M ϩ Hϩ]. C15H16N2O (240.3): calcd. C 74.97, H 6.71, N 186 (30), 158 (40), 91 (100). C14H15NO3 (245.3): calcd. C 68.56, H
11.66; found C 74.76, H 6.65, N 11.63.
6.16, N 5.71; found C 68.45, H 6.08, N 5.49.
9-Cyano-8-(4-methoxybenzyl)-7-oxa-8-azadispiro[2.0.2.3]nonane
(5d): Column chromatography (Rf ϭ 0.34, 55 g of silica gel, 3 ϫ
17 cm column, hexane/Et2O, 10:1) of the residue obtained from
the nitrone 3d (2.5 g, 13 mmol) and bicyclopropylidene (2) (2.10 g,
2.46 mL, 26.2 mmol) according to GP1 (20 °C, 8 d) gave the cyclo-
adduct 5d (3.50 g, 100%) as a colorless solid, m.p. 70؊71 °C. IR
(KBr): ν˜ ϭ 3075 cmϪ1, 3010, 2934, 2868, 2838, 2246, 1611, 1585,
1512, 1468. 1H NMR (250 MHz): δ ϭ 0.36Ϫ0.70 (m, 4 H, cPrϪH),
0.82Ϫ1.04 (m, 4 H, cPrϪH), 3.80 (s, 3 H, OCH3), 3.81 (s, 1 H,
CH), 4.04Ϫ4.28 (m, 2 H, CH2), 6.85Ϫ6.91 (m, 2 H, Ar-H),
7.30Ϫ7.37 (m, 2 H, Ar-H) ppm. 13C NMR (50.3 MHz): δ ϭ 7.2
(CH2), 7.7 (CH2), 8.2 (CH2), 11.2 (CH2), 55.2 (CH3), 62.3 (CH),
66.5 (C), 114.0 (2 CH), 126.9 (C), 130.5 (2 CH), 159.4 (C), three
carbon atom signals were not detectable at this temperature. 13C
NMR (75.5 MHz, C2D2Cl4, 100 °C): δ ϭ 6.9 (CH2), 7.4 (CH2), 7.7
(CH2), 10.5 (CH2), 30.5 (C), 55.2 (CH3), 60.2 (CH2), 62.3 (CH),
66.2 (C), 114.1 (2 CH), 116.2 (C), 127.3 (C), 130.1 (2 CH), 159.4
(C) ppm. MS (EI): m/z (%) ϭ 270 (20) [Mϩ], 241 (8), 135 (25), 121
(100). C16H18N2O2 (270.3): calcd. C 71.09, H 6.71, N 10.36; found
C 70.97, H 6.58, N 10.12.
5-Benzyl-6-phenyl-5-azaspiro[2.3]hexane-4-one (7b): Column chro-
matography (Rf ϭ 0.15, 40 g of silica gel, 3 ϫ 14 cm column, hex-
ane/Et2O, 3:1) of the residue obtained from the isoxazolidine 5b
(1.48 g, 5.08 mmol) and TFA (698 mg, 0.472 mL, 6.12 mmol) in
acetonitrile (32 mL) according to GP2 (3 h) gave the β-lactam 7b
(1.0 g, 75%) as a colorless solid, m.p. 64Ϫ65 °C. IR (KBr): ν˜ ϭ
3029 cmϪ1, 1745, 1653, 1559, 1494, 1456. 1H NMR (250 MHz):
δ ϭ 0.37Ϫ0.43 (ddd, J ϭ 10.0, 7.5, 5.0 Hz, 1 H, cPrϪH), 1.01Ϫ1.06
(ddd, J ϭ 10.0, 7.5, 5.0 Hz, 1 H, cPrϪH), 1.09Ϫ1.18 (ddd, J ϭ
10.0, 7.5, 5.0 Hz, 1 H, cPrϪH), 1.24Ϫ1.32 (ddd, J ϭ 10.0, 7.5,
5.0 Hz, 1 H, cPrϪH), 3.85 (d, J ϭ 15.0 Hz, 1 H, CH2), 4.48 (s, 1
H, CH), 4.88 (d, J ϭ 15.0 Hz, 1 H, CH2), 7.15Ϫ7.21 (m, 4 H, Ar-
H), 7.24Ϫ7.43 (m, 6 H, Ar-H) ppm. 13C NMR (62.9 MHz): δ ϭ
7.2 (CH2), 8.2 (CH2), 40.3 (C), 44.5 (CH2), 61.4 (CH), 127.5 (CH),
127.6 (CH), 128.4 (4 CH), 128.6 (2 CH), 128.7 (2 CH), 135.8 (C),
136.3 (C), 172.4 (C) ppm. MS (EI): m/z (%) ϭ 263 (36) [Mϩ], 172
(10), 130 (100), 129 (85), 115 (42), 91 (65). C18H17NO (263.3):
calcd. C 82.10, H 6.51, N 5.32; found C 82.0, H 6.25, N 5.12.
5-Benzyl-6-oxo-5-azaspiro[2.3]hexane-4-carbonitrile (7c): Column
chromatography (Rf ϭ 0.11, 41 g of silica gel, 3 ϫ 12 cm column,
hexane/Et2O, 2:1) of the residue obtained from the isoxazolidine 5c
(627 mg, 2.61 mmol) and TFA (357 mg, 0.24 mL, 3.13 mmol) in
acetonitrile (15 mL) according to GP2 (12 h) gave the β-lactam 7c
(415 mg, 75%) as a colorless oil. IR (film): ν˜ ϭ 3065 cmϪ1, 3032,
3009, 2923, 2243, 1772, 1496, 1456, 1382, 1355. 1H NMR
(300 MHz): δ ϭ 1.17Ϫ1.29 (m, 2 H, cPrϪH), 1.32Ϫ1.44 (m, 2 H,
cPrϪH), 4.14 (s, 1 H, CH), 4.25 (d, J ϭ 15.1 Hz, 1 H, CH2), 4.81
(d, J ϭ 15.1 Hz, 1 H, CH2), 7.27Ϫ7.42 (m, 5 H, Ar-H) ppm. 13C
NMR (75.5 MHz): δ ϭ 8.2 (CH2), 9.1 (CH2), 38.3 (C), 46.0 (CH2),
46.7 (CH), 115.6 (C), 128.3 (CH), 128.4 (2 CH), 129.0 (2 CH),
133.9 (C), 169.8 (C) ppm. MS (EI): m/z (%) ϭ 212 (85) [Mϩ], 183
(32), 122 (32), 91 (100), 80 (45), 69 (50). C13H12N2O (212.25): calcd.
C 73.56, H 5.70, N 13.20; found C 73.74, H 5.77, N 13.08.
8-Methyl-9-(pyridin-2-yl)-7-oxa-8-azadispiro[2.0.2.3]nonane
(5f):
Column chromatography (Rf ϭ 0.20, 54 g of silica gel, 4 ϫ 10 cm
column, hexane/Et2O, 2:1) of the residue obtained from the nitrone
3f (3.0 g, 22.0 mmol) and bicyclopropylidene (2) (2.86 g, 3.35 mL,
36 mmol) according to GP1 (60 °C, 36 d) gave the cycloadduct 5f
(3.39 g, 71%) as a colorless oil. IR (film): ν˜ ϭ 3073 cmϪ1, 3001,
2956, 2871, 2777, 1590, 1570, 1472, 1434. 1H NMR (250 MHz):
δ ϭ 0.03Ϫ0.18 (m, 2 H, cPrϪH), 0.33Ϫ0.42 (m, 2 H, cPrϪH),
0.58Ϫ0.62 (ddd, J ϭ 10.0, 5.0, 5.0 Hz, 1 H, cPrϪH), 0.90Ϫ0.99
(m, 3 H, cPrϪH), 2.90 (s, 3 H, NCH3), 4.07 (s, 1 H, CH), 7.17Ϫ7.20
(m, 1 H, Ar-H), 7.68Ϫ7.71 (m, 2 H, Ar-H), 8.44Ϫ8.47 (m, 1 H,
Ar-H) ppm. 13C NMR (62.9 MHz): δ ϭ 5.9 (CH2), 6.5 (CH2), 9.0
(CH2), 9.6 (CH2), 33.1 (C), 45.7 (CH), 66.5 (C), 79.7 (CH3), 122.5
(CH), 122.8 (CH), 136.8 (CH), 148.3 (CH), 159.3 (C) ppm. MS
(EI): m/z (%) ϭ 216 (2) [Mϩ], 201 (5), 187 (18), 159 (82), 145 (48),
130 (100), 119 (45), 92 (20), 78 (55), 42 (35). HRMS (EI) calcd. for
C13H16N2O 216.1263 [Mϩ], found 216.1263. C13H16N2O (216.3):
calcd. C 72.19, H 7.46; found C 72.45, H 7.79.
5-(4-Methoxybenzyl)-6-oxo-5-azaspiro[2.3]hexane-4-carbonitrile
(7d): Column chromatography (Rf ϭ 0.10, 44 g of silica gel, 3 ϫ
13 cm column, hexane/Et2O, 1.5:1) of the residue obtained from
the isoxazolidine 5d (2.00 g, 7.40 mmol) and TFA (1.01 g, 0.68 mL,
8.88 mmol) in acetonitrile (45 mL) according to GP2 (12 h) gave
the β-lactam 7d (1.68 g, 94%) as a colorless solid, m.p. 54Ϫ56 °C.
IR (KBr): ν˜ ϭ 3003 cmϪ1, 2973, 2913, 2867, 2841, 2249, 1754,
1613, 1585, 1515. 1H NMR (250 MHz): δ ϭ 1.14Ϫ1.27 (m, 2 H,
cPrϪH), 1.30Ϫ1.44 (m, 2 H, cPrϪH), 3.80 (s, 3 H, OCH3), 4.10 (s,
1 H, CH), 4.18 (d, J ϭ 15.0 Hz, 1 H, CH2), 4.75 (d, J ϭ 15.0 Hz,
1 H, CH2), 6.84Ϫ6.93 (m, 2 H, Ar-H), 7.20Ϫ7.26 (m, 2 H, Ar-H)
Preparation of β-Lactams 7a؊f. General Procedure (GP) 2: Tri-
fluoroacetic acid (TFA) was added to the solution of the respective
isoxazolidine 5 in acetonitrile, and the resulting mixture was stirred
at 70 °C for the indicated time. After cooling to ambient tempera-
ture, the mixture was filtered through a pad of Celite, concentrated
under reduced pressure, and the crude product was purified by col-
umn chromatography on silica gel.
Methyl 5-Benzyl-6-oxo-5-azaspiro[2.3]hexane-4-carboxylate (7a): ppm. 13C NMR (62.9 MHz): δ ϭ 8.2 (CH2), 9.0 (CH2), 38.2 (C),
Column chromatography (Rf ϭ 0.21, 40 g of silica gel, 3 ϫ 14 cm
45.5 (CH2), 46.4 (CH), 55.2 (CH3), 114.3 (2 CH), 115.7 (C), 125.9
column, hexane/Et2O, 1:1) of the residue obtained from the isox-
(C), 129.8 (2 CH), 159.5 (C), 169.6 (C) ppm. MS (EI): m/z (%) ϭ
azolidine 5a (1.41 g, 5.16 mmol) and TFA (0.710 g, 0.480 mL, 242 (40) [Mϩ], 213 (15), 121 (100). C14H14N2O2 (242.3): calcd. C
6.22 mmol) in acetonitrile (32 mL) according to GP2 (12 h) gave 69.41, H 5.82, N 11.56; found C 69.14, H 5.61, N 11.37.
4162
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2004, 4158Ϫ4166