´
S. Mayer, J.-Y. Merour, B. Joseph, G. Guillaumet
FULL PAPER
tained without further purification as a beige solid; m.p. 139Ϫ140
Ethyl
11-Benzyl-9-[(ethoxycarbonyl)methyl]-1-oxo-1,2,3,9,10,11-
°C (CH2Cl2). IR (KBr): ν˜ ϭ 3600Ϫ2800, 1767, 1710, 1694 cmϪ1
.
hexahydro[1,4]oxazino[3,2-f]pyrrolo[3,2,1-ij]quinoline-5-carboxylate
1H NMR (250 MHz, CDCl3 ϩ D2O): δ ϭ 1.24 (t, J ϭ 7.1 Hz, 3 (25): Compound 25 was prepared in 86% yield from 23 according
H, CH3), 1.36 (t, J ϭ 7.1 Hz, 3 H, CH3), 2.71 (t, J ϭ 7.1 Hz, 2 H, to the procedure for the synthesis of 24; m.p. 151Ϫ152 °C (H2O).
CH2), 3.63 (d, J ϭ 4.1 Hz, 2 H, CH2N), 4.18Ϫ4.32 (m, 2 H, IR (KBr): ν˜ ϭ 1733, 1705, 1673 cmϪ1 1H NMR (250 MHz,
CH2O), 4.30 (q, J ϭ 7.1 Hz, 2 H, CH2O), 4.43 and 4.57 (d, J ϭ CDCl3): δ ϭ 1.25 (t, J ϭ 7.2 Hz, 3 H, CH3), 1.39 (t, J ϭ 7.1 Hz,
.
16.0 Hz, 1 H, NCH2Ph), 4.60 (t, J ϭ 7.1 Hz, 2 H, NCH2), 4.85 (t, 3 H, CH3), 2.51 (dd, J ϭ 15.9, 6.1 Hz, 1 H, CH2CO); 2.71 (dd, J ϭ
J ϭ 4.1 Hz, 1 H, OCH), 6.53 (s, 1 H, HAr), 7.15 (s, 1 H, HAr), 7.16 15.9, 7.1 Hz, 1 H, CH2CO), 2.93 (m, 2 H, CH2CO), 3.10 (dd, J ϭ
(s, 1 H, HAr), 7.21Ϫ7.35 (m, 5 H, HAr). 13C NMR (62.90 MHz, 12.9, 9.6 Hz, 1 H, CH2N), 3.42 (dd, J ϭ 12.9, 2.5 Hz, 1 H, CH2N),
CDCl3): δ ϭ 14.4 (CH3), 14.6 (CH3), 34.8 (CH2), 40.3 (CH2), 49.1 4.16 (q, J ϭ 7.2 Hz, 2 H, CH2O), 4.35 (q, J ϭ 7.1 Hz, 2 H, CH2O),
(CH2), 55.7 (CH2), 60.4 (CH2), 61.9 (CH2), 72.7 (OCH), 92.1 (CH),
108.3 (CH), 111.3 (CH), 118.3 (C), 125.4 (C), 127.4 (2 CH), 127.7 4.70 (dd, J ϭ 13.5, 7.2 Hz, 1 H, NCH2), 4.76 (d, J ϭ 15.1 Hz, 1
(CH), 129.0 (2 CH), 135.6 (C), 136.1 (C), 137.5 (C), 140.3 (C), H, NCH2Ph), 4.81 (dd, J ϭ 13.5, 6.9 Hz, 1 H, NCH2), 7.15 (s, 1
162.1 (CϭO), 169.7 (CϭO), 180.2 (CϭO). MS (IS): m/z ϭ 481 [Mϩ H, HAr), 7.28 (s, 1 H, HAr), 7.25Ϫ7.39 (m, 5 H, HAr). 13C NMR
4.30Ϫ4.42 (m, 1 H, OCH), 4.43 (d, J ϭ 15.1 Hz, 1 H, NCH2Ph),
ϩ 1]. C26H28N2O7 (480.5): calcd. C 64.99, H 5.87, N 5.83; found
C 64.60, H 6.04, N 6.00.
(62.90 MHz, CDCl3): δ ϭ 14.4 (CH3), 14.6 (CH3), 38.3 (CH2), 39.5
(CH2), 42.6 (CH2), 51.9 (CH2), 60.6 (CH2), 61.1 (CH2), 61.6 (CH2),
68.5 (OCH), 107.1 (C), 110.6 (CH), 114.8 (CH), 117.4 (C), 126.3
(C), 127.6 (CH), 128.7 (4 CH), 137.2 (C), 137.5 (C), 138.8 (C),
143.9 (C), 161.9 (CO), 170.0 (CO), 189.9 (CO). MS (IS): m/z ϭ 477
[Mϩ ϩ 1]. C27H28N2O6 (476.5): calcd. C 68.05, H 5.92, N 5.88;
found C 67.74, H 6.03, N 5.71.
3-{2-[(Ethoxycarbonyl)methyl]-4-benzyl-7-(ethoxycarbonyl)-2,3,4,6-
tetrahydro[1,4]oxazino[2,3-f]indol-6-yl}propanoic Acid (23): Com-
pound 23 was prepared in 97% yield from 21 according to the pro-
cedure for the synthesis of 22; m.p. 139Ϫ140 °C (CH2Cl2). IR
(KBr): ν˜ ϭ 3500Ϫ2500, 1739, 1694 cmϪ1 1H NMR (250 MHz,
.
CDCl3 ϩ D2O): δ ϭ 1.27 (t, J ϭ 7.2 Hz, 3 H, CH3), 1.36 (t, J ϭ
7.1 Hz, 3 H, CH3), 2.62 (dd, J ϭ 15.8, 6.6 Hz, 1 H, CH2CO), 2.71
(t, J ϭ 7.3 Hz, 2 H, CH2), 2.81 (dd, J ϭ 15.8, 6.7 Hz, 1 H, CH2CO),
3.32 (dd, J ϭ 11.6, 7.2 Hz, 1 H, CH2N), 3.50 (dd, J ϭ 11.6, 2.5 Hz,
1 H, CH2N), 4.18 (q, J ϭ 7.2 Hz, 2 H, CH2O), 4.30 (q, J ϭ 7.1 Hz,
2 H, CH2O), 4.49 and 4.57 (d, J ϭ 16.3 Hz, 1 H, NCH2Ph), 4.61
(t, J ϭ 7.3 Hz, 2 H, NCH2), 4.58Ϫ4.68 (m, 1 H, OCH), 6.50 (s, 1
H, HAr), 7.02 (s, 1 H, HAr), 7.12 (s, 1 H, HAr), 7.22Ϫ7.36 (m, 5 H,
HAr). 13C NMR (62.90 MHz, CDCl3): δ ϭ 14.4 (CH3), 14.6 (CH3),
34.7 (CH2), 38.2 (CH2), 40.3 (CH2), 51.8 (CH2), 55.6 (CH2), 60.4
(CH2), 61.1 (CH2), 70.1 (CH), 91.3 (CH), 108.0 (CH), 111.2 (CH),
117.8 (C), 125.1 (C), 127.3 (2 CH), 127.6 (CH), 129.0 (2 CH), 135.7
(C), 136.3 (C), 137.7 (C), 140.7 (C), 162.1 (CϭO), 170.5 (CϭO),
176.6 (CϭO). MS (IS): m/z ϭ 495 [Mϩ ϩ 1]. C27H30N2O7 (494.5):
calcd. C 65.58, H 6.11, N 5.66; found C 65.27, H 6.29, N 5.83.
Diethyl
1-Oxo-1,2,3,9,10,11-hexahydro[1,4]oxazino[3,2-f]pyrrolo-
suspension of 24
[3,2,1-ij]quinoline-5,9-dicarboxylate (26):
A
(500 mg, 1.08 mmol) and Pd/C (10%, 50 mg) in ethyl acetate
(15 mL) was shaken in a Parr apparatus under 3 atm of hydrogen
at room temperature for 2 h. The catalyst was filtered off and the
filtrate was concentrated in vacuo to give 26 (399 mg, 100%) as a
yellow solid; m.p. 209Ϫ210 °C (ethyl acetate). IR (KBr): ν˜ ؍
3332,
1745, 1689, 1638 cmϪ1. H NMR (250 MHz, CDCl3): δ ϭ 1.29 (t,
1
J ϭ 7.2 Hz, 3 H, CH3), 1.38 (t, J ϭ 7.1 Hz, 3 H, CH3), 2.97 (t, J ϭ
7.1 Hz, 2 H, CH2CO), 3.72 (ddd, J ϭ 12.6, 5.7, 2.5 Hz, 1 H,
CH2N), 3.81 (ddd, J ϭ 12.6, 3.6, 2.7 Hz, 1 H, CH2N), 4.26 (q, J ϭ
7.2 Hz, 2 H, CH2O), 4.33 (q, J ϭ 7.1 Hz, 2 H, CH2O), 4.66Ϫ4.81
(m, 3 H, NCH2 ϩ OCH), 7.13 (s, 1 H, HAr), 7.29 (s, 1 H, HAr),
8.36 (br. s, 1 H, NH). 13C NMR (62.90 MHz, CDCl3) δ 14.3 (CH3),
14.6 (CH3), 37.9 (CH2), 41.6 (CH2), 43.2 (CH2), 60.4 (CH2), 62.0
(CH2), 71.3 (CH), 100.4 (C), 112.0 (CH), 114.0 (C), 115.3 (CH),
125.4 (C), 137.0 (C), 137.9 (C), 138.5 (C), 162.0 (CϭO), 168.8 (Cϭ
O), 193.4 (CϭO). MS (IS): m/z ؍
373 [Mϩ ϩ 1]. C19H20N2O6
(372.4): calcd. C 61.28, H 5.41, N 7.52; found C 61.62, H 5.35,
N 7.48.
Diethyl 11-Benzyl-1-oxo-1,2,3,9,10,11-hexahydro[1,4]oxazino[3,2-
f]pyrrolo[3,2,1-ij]quinoline-5,9-dicarboxylate (24): A freshly pre-
pared solution of PPSE (2.67 g of phosphorus pentoxide and
16 mL of hexamethyldisiloxane in 1,2-dichloroethane, stirred at 90
°C until complete dissolution of P2O5 with subsequent evaporation
of solvent) was added to a solution of acid 22 (1.10 g, 2.30 mmol)
in 1,2-dichloroethane (10 mL). The reaction mixture was stirred at
reflux for 2 h. After cooling and evaporation of the solvent, the
residue was dissolved in DMF (5 mL) and H2O (5 mL). Neutralis-
ation of the medium with a saturated NaHCO3 solution afforded
a yellow precipitate, which was filtered, washed with H2O and dried
over P2O5 to provide 24 (925 mg, 87%); m.p. 159Ϫ160 °C (H2O).
Ethyl
9-[(Ethoxycarbonyl)methyl]-1-oxo-1,2,3,9,10,11-hexahydro-
(27):
[1,4]oxazino[3,2-f]pyrrolo[3,2,1-ij]quinoline-5-carboxylate
Compound 27 was prepared in quantitative yield from 25 accord-
ing to the procedure for the synthesis of 26; m.p. 157Ϫ158 °C (ethyl
acetate). IR (KBr): ν˜ ϭ 3330, 1736, 1700, 1645 cmϪ1 1H NMR
.
(250 MHz, CDCl3): δ ϭ 1.29 (t, J ϭ 7.2 Hz, 3 H, CH3), 1.38 (t,
J ϭ 7.1 Hz, 3 H, CH3), 2.63 (dd, J ϭ 15.9, 6.3 Hz, 1 H, CH2CO),
2.79 (dd, J ϭ 15.9, 6.8 Hz, 1 H, CH2CO), 2.97 (t, J ϭ 7.1 Hz, 2
H, CH2CO), 3.39 (ddd, J ϭ 12.4, 7.8, 1.3 Hz, 1 H, CH2N), 3.68
(ddd, J ϭ 12.4, 3.9, 3.8 Hz, 1 H, CH2N), 4.21 (q, J ϭ 7.2 Hz, 2 H,
CH2O), 4.33 (q, J ϭ 7.1 Hz, 2 H, CH2O), 4.45Ϫ4.54 (m, 1 H,
OCH), 4.72 (t, J ϭ 7.1 Hz, 2 H, NCH2) 7.11 (s, 1 H, HAr), 7.14
(1s, 1 H, HAr), 8.41 (br. s, 1 H, NH). 13C NMR (62.90 MHz,
CDCl3): δ ϭ 14.4 (CH3), 14.6 (CH3), 38.0 (CH2), 38.0 (CH2), 43.4
(CH2), 44.0 (CH2), 60.4 (CH2), 61.2 (CH2), 69.4 (CH), 100.2 (C),
112.1 (CH), 113.2 (C), 115.1 (CH), 125.2 (C), 137.2 (C), 138.0 (C),
139.2 (C), 162.0 (CϭO), 170.2 (CϭO), 193.3 (CϭO). MS (IS):
m/z ϭ 387 [Mϩ ϩ 1]. C20H22N2O6 (386.41): calcd. C 62.17, H 5.74,
N 7.25; found C 61.76, H 5.60, N 7.42.
IR (KBr): ν˜ ϭ 1740, 1699, 1665 cmϪ1 1H NMR (250 MHz,
.
CDCl3): δ ϭ 1.27 (t, J ϭ 7.1 Hz, 3 H, CH3), 1.39 (t, J ϭ 7.2 Hz,
3 H, CH3), 2.91Ϫ2.98 (m, 2 H, CH2CO), 3.32 (dd, J ϭ 13.5, 8.3 Hz,
1 H, CH2N), 3.56 (dd, J ϭ 13.5, 2.9 Hz, 1 H, CH2N), 4.15Ϫ4.30
(m, 2 H, CH2O), 4.35 (q, J ϭ 7.2 Hz, 2 H, CH2O), 4.42 (d, J ϭ
15.3 Hz, 1 H, NCH2Ph), 4.49 (dd, J ϭ 8.3, 2.9 Hz, 1 H, OCH),
4.67 (d, J ϭ 15.3 Hz, 1 H, NCH2Ph), 4.63Ϫ4.74 (m, 1 H, NCH2),
4.78Ϫ4.88 (m, 1 H, NCH2), 7.18 (s, 1 H, HAr), 7.46 (s, 1 H, HAr),
7.27Ϫ7.44 (m, 5 H, HAr). 13C NMR (62.90 MHz, CDCl3): δ ϭ 14.2
(CH3), 14.5 (CH3), 39.4 (CH2), 42.4 (CH2), 48.6 (CH2), 60.6 (CH2),
61.7 (CH2), 61.8 (CH2), 69.7 (CH), 107.7 (C), 110.4 (CH), 115.5
(CH), 118.2 (C), 126.8 (C), 127.6 (CH), 128.6 (4 CH), 135.9 (C),
137.1 (C), 138.6 (C), 142.6 (C), 161.7 (CϭO), 168.7 (CϭO), 189.9
(CϭO). MS (IS): m/z ϭ 463 [Mϩ ϩ 1]. C26H26N2O6 (462.5): calcd.
C 67.52, H 5.67, N 6.06; found C 67.15, H 5.49, N 5.92.
Ethyl
2,2-Bis[2-(benzyloxycarbonyl)ethyl]-9-[(ethoxycarbonyl)me-
thyl]-1-oxo-1,2,3,9,10,11-hexahydro[1,4]oxazino[3,2-f]pyrrolo[3,2,1-
1652
Eur. J. Org. Chem. 2002, 1646Ϫ1653