2710
K. Inamoto et al. / Tetrahedron 63 (2007) 2695–2711
(42.8 mg, 0.18 mmol) in DMF (5 mL) at 0 ꢀC. After stirring
for 10 min at the same temperature, 1,4-dibromobutane
(0.98 g, 4.6 mmol) was added at 0 ꢀC and stirred for 1.5 h
at room temperature. The mixture was quenched with phos-
phate buffer solution (pH 6.86) and the mixturewas extracted
with ethyl acetate (5 mLꢂ3). The combined organic solution
was washed with brine (5 mL), and dried over MgSO4. The
solvent was evaporated and the residue was purified by silica
gel column chromatography [hexane–ethyl acetate (4:1)] to
afford 18a (36.7 mg, 54%) and 18b (24.8 mg, 37%) as color-
less solids. Compound 18a: IR n (film, cmꢁ1) 1728, 1269; 1H
NMR (400 MHz, CDCl3) d 1.45 (3H, t, J¼7.2 Hz), 1.87 (2H,
quint, J¼7.0 Hz), 2.10 (2H, quint, J¼7.0 Hz), 2.48 (3H, s),
3.40 (2H, t, J¼7.0 Hz), 3.96 (3H, s), 4.41 (2H, t,
J¼7.0 Hz), 4.48 (2H, q, J¼7.2 Hz), 6.43 (1H, s), 6.79 (1H,
s); 13C NMR (100 MHz, CDCl3) d 14.5, 22.4, 28.2, 29.7,
32.8, 48.6, 55.6, 61.1, 101.4, 104.3, 112.5, 135.3, 138.9,
142.8, 153.5, 162.4; MS m/z 370 (M++2, 43), 368 (M+, 43),
243 (100); HRMS calcd for C16H2179BrN2O3: 368.0736,
found: 368.0747. Compound 18b: IR n (film, cmꢁ1) 1705,
1236; 1H NMR (400 MHz, CDCl3) d 1.46 (3H, t,
J¼7.2 Hz), 1.87 (2H, quint, J¼7.0 Hz), 2.11 (2H, quint,
J¼7.0 Hz), 2.42 (3H, s), 3.40 (2H, t, J¼7.0 Hz), 3.90 (3H,
s), 4.46 (2H, q, J¼7.2 Hz), 4.70 (2H, t, J¼7.0 Hz), 6.33
(1H, s), 7.08 (1H, s); 13C NMR (100 MHz, CDCl3) d 14.3,
22.4, 29.4, 29.6, 32.8, 52.0, 55.2, 61.5, 104.6, 108.9, 113.1,
125.1, 137.1, 149.6, 152.4, 161.0; MS m/z 370 (M++2, 29),
368 (M+, 29), 289 (100); HRMS calcd for C16H2179BrN2O3:
368.0736, found: 368.0747.
The solvent was evaporated under ice-water bath cooling
to afford 19 (26.5 mg), which was treated with BBr3
(1.0 M solution in hexane, 0.79 mL, 0.79 mmol) in dichloro-
methane (2 mL) and worked up as same way as described
above to afford nigellicine (6) (15.1 mg, 86% from 18b).
References and notes
1. Cerecetto, H.; Gerpe, A.; Gonzalez, M.; Aran, V. J.; de Ocariz,
C. O. Mini-Rev. Med. Chem. 2005, 5, 869–878.
2. (a) Steffan, R. J.; Matelan, E.; Ashwell, M. A.; Moore, W. J.;
Solvibile, W. R.; Trybulski, E.; Chadwick, C. C.; Chippari,
S.; Kenney, T.; Eckert, A.; Borges-Marcucci, L.; Keith, J. C.;
Xu, Z.; Mosyak, L.; Harnish, D. C. J. Med. Chem. 2004, 47,
6435–6438; (b) Angelis, M. D.; Stossi, F.; Carlson, K. A.;
Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med.
Chem. 2005, 48, 1132–1144.
3. Zhang, H.-C.; Derian, C. K.; McComsey, D. F.; White, K. B.;
Ye, H.; Hecker, L. R.; Li, J.; Addo, M. F.; Croll, D.; Eckardt,
A. J.; Smith, C. E.; Li, Q.; Cheung, W.-M.; Conway, B. R.;
Emanuel, S.; Demarest, K. T.; Andrade-Gordon, P.; Damiano,
B. P.; Maryanoff, B. E. J. Med. Chem. 2005, 48, 1725–1728.
4. (a) Fludzinski, P.; Evrard, D. A.; Bloomquist, W. E.; Lacefield,
W. B.; Pfeifer, W.; Jones, N. D.; Deeter, J. B.; Cohen, M. L.
J. Med. Chem. 1987, 30, 1535–1537; (b) Harada, H.; Morie,
T.; Hirokawa, Y.; Kato, S. Tetrahedron: Asymmetry 1997, 8,
2367–2374; (c) May, J. A.; Dantanarayana, A. P.; Zinke,
P. W.; McLaughlin, M. A.; Sharif, N. A. J. Med. Chem. 2006,
49, 318–328.
4.7.7. Nigellicine (6 from 18a or 18b). From 18a: a solution
of the indazole 18a (4.2 mg, 0.011 mmol) in ethanol (4 mL)
was then bubbled with CO2 gas for 30 min and heated at
85 ꢀC in a sealed tube for 48 h. The solvent was evaporated
under ice-water bath cooling to afford 19 (5.6 mg); 1H NMR
(600 MHz, CDCl3) d 1.47 (3H, t, J¼7.2 Hz), 2.45–2.52 (4H,
m), 2.56 (3H, s), 3.97 (3H, s), 4.57 (2H, q, J¼7.2 Hz), 4.93
(2H, t, J¼6.0 Hz), 4.98 (2H, t, J¼6.0 Hz), 6.63 (1H, s), 7.22
(1H, s); 13C NMR (150 MHz, CDCl3) d 13.9, 18.9, 19.5,
23.1, 48.0, 50.4, 56.0, 63.9, 101.8, 107.4, 109.6, 131.7,
141.6, 147.9, 153.2, 157.4; FABMS m/z 289 (M+ꢁBr).
5. (a) Han, W.; Pelletier, J. C.; Hodge, C. N. Bioorg. Med. Chem.
Lett. 1998, 8, 3615–3620; (b) Patel, M.; Rodgers, J. D.;
McHugh, R. J., Jr.; Johnson, B. L.; Cordova, B. C.; Klaba,
R. M.; Bacheler, L. T.; Erickson-Viitanen, S.; Ko, S. S.
Bioorg. Med. Chem. Lett. 1999, 9, 3217–3220.
6. Showalter, H. D. H.; Angelo, M. M.; Berman, E. M.; Kanter,
G. D.; Ortwine, D. F.; Ross-Kesten, S. G.; Sercel, A. D.;
Turner, W. R.; Werbel, L. M.; Worth, D. F.; Elslager, E. F.;
Leopald, W. R.; Shillis, J. L. J. Med. Chem. 1988, 31, 1527–
1539.
7. For the construction of indazole ring system by N1–N2 bond
formation, see: (a) Armour, M.-A.; Cadogan, J. I. G.; Grace,
D. S. B. J. Chem. Soc., Perkin Trans. 2 1975, 1185–1189; (b)
Ardakani, M. A.; Smalley, R. K.; Smith, R. H. Synthesis
1979, 308–309; (c) Akazome, M.; Kondo, T.; Watanabe, Y.
J. Org. Chem. 1994, 59, 3375–3380; (d) Frontana-Uribe, B. A.;
Moinet, C. Tetrahedron 1998, 54, 3197–3206; (e) O’Dell,
D. K.; Nicholas, K. M. Heterocycles 2004, 63, 373–382.
8. For the construction of indazole ring system by N2–C3 bond
formation, see: (a) Alberti, A.; Bedogni, N.; Benaglia, M.;
Leardini, R.; Nanni, D.; Pedulli, G. F.; Tundo, A.; Zanardi,
G. J. Org. Chem. 1992, 57, 607–613; (b) Dell’Erba, C.; Novi,
M.; Petrillo, G.; Tavani, C. Tetrahedron 1994, 50, 3529–3536.
9. For the construction of indazole ring system by N1–C7a bond
formation, see: (a) Zhenqi, Z.; Tongsheng, X.; Xiaonai, C.;
Yuzhu, Q.; Zheng, Z.; Hongwen, H. J. Chem. Soc., Perkin
Trans. 1 1993, 1279–1280; (b) Halley, F.; Sava, X. Synth.
Commun. 1997, 27, 1199–1207; (c) Lukin, K.; Hsu, M. C.;
Fernando, D.;Leanna,M. R. J. Org. Chem. 2006, 71, 8166–8172.
10. (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1348–1350; (b) Louie, J.;
Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609–3612; For
reviews on Pd-catalyzed amination reaction, see: (c) Wolfe,
BBr3 (1.0 M solution in hexane, 0.17 mL, 0.17 mmol) was
dropped into a solution of 19 in dichloromethane (3 mL) at
0 ꢀC and stirred at room temperature for 3.5 h. H2O was
slowly added to the mixture at 0 ꢀC. The mixture was
extracted with 10% methanol in dichloromethane (5 mLꢂ4)
and the organic solution was dried over MgSO4. The solvent
was evaporated and the residue was washed with hexane
(2 mLꢂ2), diethyl ether (2 mLꢂ2), and ethyl acetate
(2 mLꢂ2) and dried in vacuo to give nigellicine (6)
(2.8 mg, >99% from 18a); IR n (KBr, cmꢁ1) 3422, 2922,
2853, 1630, 1578, 1516, 1458, 1408, 1283, 1261; 1H NMR
(400 MHz, CDCl3–CD3OD¼5:1) d 2.26–2.37 (4H, m), 2.47
(3H, s), 4.44 (2H, t, J¼6.0 Hz), 5.17 (2H, t, J¼6.0 Hz), 6.54
(1H, s), 6.66 (1H, s); 13C NMR (100 MHz, CDCl3–
CD3OD¼5:1) d 19.2, 19.9, 22.5, 46.6, 49.8, 97.5, 110.4,
110.5, 137.9, 141.6, 148.0, 153.3, 159.5; FABMS m/z 247
(M++1).
From 18b: a solution of the indazole 18b (26.3 mg,
0.071 mmol) in ethanol (4 mL) was bubbled with CO2 gas
for 30 min and heated at 85 ꢀC in a sealed tube for 48 h.