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P. Barraja et al. / Tetrahedron Letters 50 (2009) 4182–4184
2. Jakobs, A. E.; Piette, J. J. Photochem. Photobiol. B. 1994, 22, 9–15.
3. Jakobs, A. E.; Piette, J. J. Med. Chem. 1995, 38, 869–874.
4. Rodighiero, P.; Guiotto, A.; Chilin, A.; Bordin, F.; Baccichetti, F.; Carlassare, F.;
Vedaldi, D.; Caffieri, S.; Pozzan, A.; Dall’Acqua, F. J. Med. Chem. 1996, 39, 1293–
1302.
5. Barraja, P.; Diana, P.; Lauria, A.; Montalbano, A.; Almerico, A. M.; Dattolo, G.;
Cirrincione, G.; Viola, G.; Dall’Acqua, F. Bioorg. Med. Chem. Lett. 2003, 13, 2809–
2811.
J = 8.8 Hz, H-6), 7.11 (1H, d, J = 8.8 Hz, H-5), 11.60 (1H, s, NH); 13C NMR (DMSO-
d6, 50 MHz): d 12.9 (CH3), 14.0 (CH3), 14.1 (CH3), 30.2 (CH3), 35.2 (CH2), 60.2
(CH2), 60.5 (CH2), 72.8 (CH), 101.9 (C), 104.7 (CH), 112.2 (CH), 114.2 (C), 118.5
(C), 133.4 (C), 137.0 (C), 146.8 (C), 165.0 (CO), 167.1 (CO), 169.4 (CO). Anal.
C19H22N2O6: C, 60.95; H, 5.92; N, 7.48. Found: C, 61.12; H, 6.15; N, 7.18.
Data for methyl 3-(2-ethoxy-2-oxoethyl)-7,8-dimethyl-2-oxo-1,2,3,7-tetrahydro
[1,4]oxazino[3,2-e]indole-9-carboxylate 5d: white solid; mp 144–145 °C; Yield
65%; IR (CHBr3): 3255–2950 (NH), 1732 (CO), 1689 (CO), 1657 (CO) cmꢀ1 1H
;
6. Barraja, P.; Diana, P.; Montalbano, A.; Dattolo, G.; Cirrincione, G.; Viola, G.;
Vedaldi, D.; Dall’Acqua, F. Bioorg. Med. Chem. 2006, 14, 8712–8728.
7. Barraja, P.; Sciabica, L.; Diana, P.; Lauria, A.; Montalbano, A.; Almerico, A. M.;
Dattolo, G.; Cirrincione, G.; Disarò, S.; Basso, G.; Viola, G.; Dall’Acqua, F. Bioorg.
Med. Chem. Lett. 2005, 15, 2291–2294.
8. Barraja, P.; Diana, P.; Montalbano, A.; Carbone, A.; Cirrincione, G.; Viola, G.;
Salvador, A.; Vedaldi, D.; Dall’Acqua, F. Bioorg. Med. Chem. 2008, 16, 9668–9683.
9. Thuillier, G.; Laforest, J.; Bessin, P.; Bonnet, J.; Thuillier, J. Eur. J. Med. Chem.
1975, 10, 37–42.
NMR (DMSO-d6, 200 MHz): d 1.20 (3H, t, J = 7.3 Hz, CH3), 2.65 (3H, s, CH3),
2.80–3.06 (2H, m, CH2), 3.64 (3H, s, CH3), 3.85 (3H, s, CH3), 4.11 (2H, q,
J = 7.3 Hz, CH2), 4.84–4.90 (1H, m, H-3), 6.84 (1H, d, J = 8.8 Hz, H-6), 7.08 (1H, d,
J = 8.8 Hz, H-5), 11.60 (1H, s, NH); 13C NMR (DMSO-d6, 50 MHz): d 12.9 (CH3),
14.0 (CH3), 30.2 (CH3), 35.2 (CH2), 51.7 (CH3), 60.2 (CH2), 72.8 (CH), 101.9 (C),
104.7 (CH), 112.2 (CH), 114.2 (C), 118.5 (C), 133.4 (C), 137.0 (C), 146.8 (C),
165.0 (CO), 167.1 (CO), 169.4 (CO). Anal. C18H20N2O6: C, 59.99; H, 5.59; N, 7.77.
Found: C, 60.10; H, 5.79; N, 7.50.
Data for ethyl 3-(2-ethoxy-2-oxoethyl)-7-phenyl-8-methyl-2-oxo-1,2,3,7-tetrah
ydro[1,4]oxazino[3,2-e]indole-9-carboxylate 5e: white solid; mp 142–144 °C;
10. Reusser, F. J. Antibiot. 1979, 32, 1186–1192.
11. Reusser, F. Biochemistry 1973, 12, 1136–1142.
Yield 75%; IR (CHBr3): 3232–3145 (NH), 1732 (CO), 1691 (CO), 1660 (CO) cmꢀ1
;
12. Turk, C. F.; Krapcho, J.; Michel, I. M.; Weinryb, I. J. Med. Chem 1977, 20, 729–
732.
13. Kimura, K.; Usui, Y.; Hattori, T.; Yamakawa, N.; Goto, H.; Usui, M.; Okada, S.;
Shirato, K.; Tomoda, A. Oncol. Rep. 2008, 19, 3–10.
14. Ishihara, M.; Kawase, M.; Westman, G.; Samuelsson, K.; Motohashi, N.;
Sakagami, H. Anticancer Res. 2007, 27, 4053–4057.
15. Mas, J. -M.; Rochin, C. PCT Int. Appl. WO 9724316, 1997; Chem. Abstr. 1997, 127,
108760.
1H NMR (DMSO-d6, 200 MHz): d 1.19 (3H, t, J = 7.3 Hz, CH3), 1.37 (3H, t,
J = 7.3 Hz, CH3), 2.47 (3H, s, CH3), 2.82–3.07 (2H, m, CH2), 4.10 (2H, q, J = 7.3 Hz,
CH2), 4.38 (2H, q, J = 7.3 Hz, CH2), 4.86–4.92 (1H, m, H-3), 6.47 (1H, d, J = 8.7 Hz,
H-6), 6.82 (1H, d, J = 8.7 Hz, H-5), 7.45 (2H, d, J = 6.0 Hz, H-20 and H-60), 7.58–
7.73 (3H, m, H-30, H-40 and H-50), 11.59 (1H, s, NH); 13C NMR (DMSO-d6,
50 MHz): d 14.0 (CH3), 14.1 (CH3), 14.2 (CH3), 35.2 (CH2), 60.3 (CH2), 60.9 (CH2),
72.9 (CH), 103.6 (C), 105.0 (CH), 113.0 (CH), 114.2 (C), 118.8 (C), 128.2 (CH ꢁ 2),
129.5 (CH), 130.1 (CH ꢁ 2), 134.4 (C), 135.4 (C), 137.4 (C), 146.5 (C), 165.1 (CO),
167.2 (CO), 169.4 (CO). Anal. C24H24N2O6: C, 66.04; H, 5.54; N, 6.42. Found: C,
66.28; H, 5.32; N, 6.38.
16. Ray, P. C.; Medikonduri, S.; Ramanjaneyulu, G. S. PCT Int. Appl. WO 083320,
2007; Chem. Abstr. 2007, 147, 21894.
17. Rodighiero, P.; Chilin, A.; Pastorini, G.; Guiotto, A. J. Heterocyc. Chem. 1987, 24,
Data for 3-(2-ethoxy-2-oxoethyl)-7-benzyl-8-methyl-2-oxo-1,2,3,7-tetrahydro
[1,4]oxazino[3,2-e]indole-9-carboxylic acid 5f: This compound was obtained by
heating under reflux (40 min) an ethanolic solution (20 mL) of 5a or 5b
(3 mmol) with 15% KOH (10 mL); white solid; mp 228–229 °C; Yield 80–85%,
respectively; IR (CHBr3): 3126–2884 (OH, NH), 1722 (CO), 1698 (CO), 1664
1041–1043.
18. Allen, G. R.; Pidacks, C.; Weiss, M. J. J. Am. Chem. Soc. 1966, 88, 2536–2544.
19. Everett, S. A.; Naylor, M. A.; Barraja, P.; Swann, E.; Patel, K. B.; Stratford, M. R. L.;
Hudnott, A. R.; Vojnovic, B.; Locke, R. J.; Wardman, P.; Moody, C. J. J. Chem. Soc.,
Perkin Trans. 2, 2001, 843–860.
(CO) cmꢀ1 1H NMR (DMSO-d6, 200 MHz): d 1.36 (3H, t, J = 7.1 Hz, CH3), 2.66
;
20. Preparation of 2-oxo[1,4]oxazino[3,2-e]indoles 5a-e:
A
mixture of 18a–e
(3H, s, CH3), 2.75–2.99 (2H, m, CH2), 4.36 (2H, q, J = 7.1 Hz, CH2), 4.83–4.88 (1H,
m, H-3), 5.52 (2H, s, CH2), 6.86 (1H, d, J = 8.8 Hz, H-6), 7.02 (2H, d, J = 6.0 Hz, H-
20 and H-60), 7.12 (1H, d, J = 8.8 Hz, H-5), 7.25–7.36 (3H, m, H-30, H-40 and H-50),
11.57 (1H, s, NH), 12.41 (1H, s, OH); 13C NMR (DMSO-d6, 50 MHz): d 13.0 (CH3),
14.1 (CH3), 35.3 (CH2), 46.2 (CH2), 60.7 (CH2), 73.0 (CH), 102.9 (C), 105.1 (CH),
112.7 (CH), 114.4 (C), 118.8 (C), 126.0 (CH ꢁ 2), 127.4 (CH), 128.8 (CH ꢁ 2),
133.2 (C), 136.6 (C), 137.3 (C), 146.5 (C), 165.3 (CO), 167.1 (CO), 171.0 (CO).
Anal. C23H22N2O6: C, 65.39; H, 5.25; N, 6.63. Found: C, 65.10; H, 4.90; N, 6.50.
Data for 3-(2-ethoxy-2-oxoethyl)-7,8-dimethyl-2-oxo-1,2,3,7-tetrahydro[1,4]
oxazino[3,2-e]indole-9-carboxylic acid 5g: This compound was obtained by
heating under reflux (40 min) an ethanolic solution (20 mL) of 5c or 5d
(3 mmol) with 15% KOH (10 mL); white solid; mp 251–252 °C; Yield 68–70%,
respectively; IR (CHBr3): 3153–2911 (OH, NH), 1730 (CO), 1632 (CO), 1630
(1.4 mmol) and K2CO3 (0.4 g, 2.8 mmol) in ethanol (10 mL) was stirred at
room temperature for 30 min. The mixture was poured onto crushed ice and
the solid was filtered off, dried and recrystallized from ethanol.
Data for ethyl 3-(2-ethoxy-2-oxoethyl)-7-benzyl-8-methyl-2-oxo-1,2,3,7-tetrahy
dro[1,4]oxazino[3,2-e]indole-9-carboxylate 5a: white solid; mp 166–167 °C;
Yield 82%; IR (CHBr3): 3181–3147 (NH), 1734 (CO), 1689 (CO), 1657
(CO) cmꢀ1 1H NMR (DMSO-d6, 200 MHz): d 1.18 (3H, t, J = 7.3 Hz, CH3), 1.36
;
(3H, t, J = 7.3 Hz, CH3), 2.66 (3H, s, CH3), 2.82–3.07 (2H, m, CH2), 4.10 (2H, q,
J = 7.3 Hz, CH2), 4.36 (2H, q, J = 7.3 Hz, CH2), 4.87–4.93 (1H, m, H-3), 5.52 (2H, s,
CH2), 6.85 (1H, d, J = 8.8 Hz, H-6), 7.02 (2H, d, J = 7.6 Hz, H-20 and H-60), 7.12
(1H, d, J = 8.8 Hz, H-5), 7.22–7.35 (3H, m, H-30, H-40 and H-50), 11.61 (1H, s,
NH); 13C NMR (DMSO-d6, 50 MHz): d 13.0 (CH3), 13.9 (CH3), 14.1 (CH3), 35.2
(CH2), 46.2 (CH2), 60.2 (CH2), 60.7 (CH2), 72.8 (CH), 102.9 (C), 105.1 (CH), 112.6
(CH), 114.4 (C), 119.0 (C), 126.0 (CH ꢁ 2), 127.4 (CH), 128.7 (CH ꢁ 2), 133.2 (C),
136.6 (C), 137.2 (C), 146.5 (C), 165.1 (CO), 167.1 (CO), 169.4 (CO). Anal.
C25H26N2O6: C, 66.65; H, 5.82; N, 6.22. Found: C, 66.30; H, 6.15; N, 6.10.
Data for methyl 3-(2-ethoxy-2-oxoethyl)-7-benzyl-8-methyl-2-oxo-1,2,3,7-tetra
hydro[1,4]oxazino[3,2-e]indole-9-carboxylate 5b: white solid; mp 170–171 °C;
(CO) cmꢀ1 1H NMR (DMSO-d6, 200 MHz): d 1.36 (3H, t, J = 6.5 Hz, CH3), 2.61
;
(3H, s, CH3), 2.71–2.99 (2H, m, CH2), 3.63 (3H, s, CH3), 4.30 (2H, q, J = 6.5 Hz,
CH2), 4.81–4.83 (1H, m, H-3), 6.85 (1H, d, J = 8.8 Hz, H-6), 7.06 (1H, d, J = 8.8 Hz,
H-5), 11.57 (1H, s, NH), 12.57 (1H, s, OH); 13C NMR (DMSO-d6, 50 MHz): d 12.8
(CH3), 14.1 (CH3), 30.1 (CH3), 35.3 (CH2), 60.6 (CH2), 73.1 (CH), 101.9 (C), 104.6
(CH), 112.7 (CH), 114.2 (C), 118.6 (C), 133.4 (C), 137.1 (C), 146.7 (C), 165.3 (CO),
167.1 (CO), 171.1 (CO). Anal. C17H18N2O6: C, 58.96; H, 5.24; N, 8.09. Found: C,
58.60; H, 5.45; N, 8.30.
Yield 68%; IR (CHBr3): 3221–3105 (NH), 1732 (CO), 1691 (CO), 1662 (CO) cmꢀ1
;
1H NMR (DMSO-d6, 200 MHz): d 1.18 (3H, t, J = 7.4 Hz, CH3), 2.65 (3H, s, CH3),
2.82–3.07 (2H, m, CH2), 3.89 (3H, s, CH3), 4.09 (2H, q, J = 7.4 Hz, CH2), 4.87–4.93
(1H, m, H-3), 5.52 (2H, s, CH2), 6.85 (1H, d, J = 8.5 Hz, H-6), 7.00 (2H, d,
J = 6.3 Hz, H-20 and H-60), 7.12 (1H, d, J = 8.5 Hz, H-5), 7.24–7.35 (3H, m, H-30,
H-40 and H-50), 11.58 (1H, s, NH); 13C NMR (DMSO-d6, 50 MHz): d 13.0 (CH3),
13.9 (CH3), 35.2 (CH2), 46.2 (CH2), 51.9 (CH3), 60.2 (CH2), 72.8 (CH), 102.8 (C),
105.1 (CH), 112.6 (CH), 114.4 (C), 118.8 (C), 126.0 (CH ꢁ 2), 127.4 (CH), 128.7
(CH ꢁ 2), 133.2 (C), 136.6 (C), 137.2 (C), 146.5 (C), 165.1 (CO), 167.6 (CO), 169.4
(CO). Anal. C24H24N2O6: C, 66.04; H, 5.54; N, 6.42. Found: C, 66.40; H, 5.25; N,
6.78.
Data for 3-(2-ethoxy-2-oxoethyl)-7-phenyl-8-methyl-2-oxo-1,2,3,7-tetrahydro[1,4]
oxazino[3,2-e]indole-9-carboxylic acid 5h: This compound was obtained by
heating under reflux (40 min) an ethanolic solution (20 mL) of 5e (3 mmol)
with 15% KOH (10 mL); white solid; mp 224–226 °C; Yield 58%; IR (CHBr3):
3408–2929 (OH, NH), 1697 (CO), 1656 (CO), 1637 (CO) cmꢀ1 1H NMR (DMSO-
;
d6, 200 MHz): d 1.36 (3H, t, J = 7.1 Hz, CH3), 2.40–2.52 (2H, m, CH2), 2.45 (3H, s,
CH3), 4.34 (2H, q, J = 7.1 Hz, CH2), 4.92–5.04 (1H, m, H-3), 6.43 (1H, d, J = 8.7 Hz,
H-6), 6.78 (1H, d, J = 8.7 Hz, H-5), 7.44 (2H, d, J = 6.0 Hz, H-20 and H-60), 7.62–
7.66 (3H, m, H-30, H-40 and H-50), 11.47 (1H, s, NH), 12.49 (1H, s, OH); 13C NMR
(DMSO-d6, 50 MHz): d 14.0 (CH3), 14.1 (CH3), 37.6 (CH2), 60.8 (CH2), 74.5 (CH),
99.5 (C), 103.5 (C), 104.8 (CH), 113.3 (CH), 118.9 (C), 128.2 (CH ꢁ 2), 129.4
(CH), 130.0 (CH ꢁ 2), 134.2 (C), 135.4 (C), 137.6 (C), 146.3 (C), 166.5 (CO), 167.2
(CO), 167.3 (CO). Anal. C22H20N2O6: C, 64.70; H, 4.94; N, 6.86. Found: C, 64.40;
H, 4.70; N, 6.54.
Data for ethyl 3-(2-ethoxy-2-oxoethyl)-7,8-dimethyl-2-oxo-1,2,3,7-tetrahydro
[1,4]oxazino[3,2-e]indole-9-carboxylate 5c: white solid; mp 141–142 °C; Yield
65%; IR (CHBr3): 3255–3093 (NH), 1732 (CO), 1689 (CO), 1657 (CO) cmꢀ1 1H
;
NMR (DMSO-d6, 200 MHz): d 1.20 (3H, t, J = 7.3 Hz, CH3), 1.36 (3H, t, J = 7.3 Hz,
CH3), 2.65 (3H, s, CH3), 2.80–3.06 (2H, m, CH2), 3.67 (3H, s, CH3), 4.11 (2H, q,
J = 7.3 Hz, CH2), 4.33 (2H, q, J = 7.3 Hz, CH2), 4.83–4.89 (1H, m, H-3), 6.86 (1H, d,