LETTER
New Synthesis of 3-(Nitro- and Amino)flavones
1385
(21) (a) Barros, A. I. R. N. A.; Silva, A. M. S. Magn. Reson.
Chem. 2006, 44, 1122. (b) Barros, A. I. R. N. A.; Dias,
A. F. R.; Silva, A. M. S. Monatsh. Chem. 2007, 138, 585.
(22) Deng, B.-L.; Lepoivre, J. A.; Lumière, G. Eur. J. Org. Chem.
1999, 2683.
DMSO-d6): d = 106.6 (C-3), 115.7 (Cq, J = 288.7 Hz, 4¢-
NHCOCF3), 118.6 (C-8), 121.1 (C-3¢,5¢), 123.4 (C-10),
124.9 (C-6), 125.6 (C-5), 127.4 (C-2¢,6¢), 127.9 (C-1¢), 134.4
(C-7), 139.6 (C-4¢), 154.8 (Cq, J = 37.3 Hz, 4¢-NHCOCF3),
155.7 (C-9), 162.0 (C-2), 177.2 (C-4) ppm. 19F NMR
(282.40 MHz, DMSO-d6): d = –97.39 (4¢-NHCOCF3) ppm.
ESI-MS (+): m/z (%) = 356 (21) [M + Na]+, 334 (100) [M +
1]+. Anal. Calcd for C17H10F3NO3: C, 61.27; H, 3.02; N,
4.20. Found: C, 61.06; H, 2.67; N, 4.43.
(23) Takechi, A.; Takikawa, H.; Miyake, H.; Sasaki, M. Chem.
Lett. 2006, 35, 128.
(24) (a) Olah, G. A.; Malhorta, R.; Narang, S. C. Nitration –
Methods and Mechanism; VCH: New York, 1989. (b) Ono,
N. The Nitro Group in Organic Synthesis; Wiley-VCH: New
York, 2001.
(25) (a) Salzbrunn, S.; Simon, J.; Prakash, G. K. R.; Petasis, N.
A.; Olah, G. A. Synlett 2000, 1485. (b) Prakash, G. K. R.;
Panja, C.; Mathew, T.; Surampudi, V.; Petasis, N. A.; Olah,
G. A. Org. Lett. 2004, 6, 2205. (c) Deghati, P. Y. F.;
Bieraugel, H.; Wanner, M. J.; Koomen, G. J. Tetrahedron
Lett. 2000, 41, 569. (d) Mellor, J. M.; Mittoo, S.; Parkes, R.;
Millar, R. W. Tetrahedron 2000, 8019.
(26) Crivello, J. V. J. Org. Chem. 1981, 46, 3056.
(27) Njoroge, F. G.; Vibulbhan, B.; Pinto, P.; Chang, T.-M.;
Osterman, R.; Remiszewski, S.; Del Rosario, J.; Doll, R.;
Girijavallabhan, V.; Ganguly, A. K. J. Org. Chem. 1998, 63,
445.
(28) General Procedure for the Nitration of Flavones 1a–e:
Synthesis of 3-Nitroflavones 2a–e
(31) Cunningham, B. D.; Threadgill, M. D.; Groundwater, P. W.;
Dale, I. L.; Hickman, J. A. Anticancer Drug Des. 1992, 7,
365.
(32) Evans, P. A.; Longmire, J. M. Tetrahedron Lett. 1994, 35,
8345.
(33) General Procedure for the Reduction of 3-Nitroflavones
2a–c (Method A): Synthesis of 3-Aminoflavones 8a–c
Ammonium formate (215 mg; 3.30 mmol) and Pd/C (33 mg)
were added to a solution of the 3-nitroflavone 2a–c (0.33
mmol) in acetone (5 mL), and the reaction mixture was
heated at 80 °C for 1 h. After cooling to r.t., the reaction
mixture was filtered through Celite, and the organic layer
was evaporated to dryness. The residue was purified by
column chromatography on silica gel and eluted with
CH2Cl2 to give the 3-aminoflavones 8a–c (for yield, see
Table 2).
To a solution of the appropriate flavone 1a–e (0.38 mmol) in
the requisite solvent (20 mL in total), cooled in an ice bath,
NH4NO3 and TFAA were added, and the reaction mixture
was stirred under conditions indicated in Table 1. After the
appropriate reaction time, the reaction mixture was poured
into H2O (20 mL), and extracted with CHCl3 (3 × 20 mL).
The combined organic extracts were dried over Na2SO4,
filtered, and evaporated to dryness. The mixture was purified
by silica gel column chromatography eluting with mixtures
of CH2Cl2–light PE of increasing polarity to afford the
3-nitroflavones and byproducts (Table 1).
(34) General Procedure for the Reduction of 3-Nitroflavones
2a–e (Method B): Synthesis of 3-Aminoflavones 8a–e
To a solution of the 3-nitroflavone 2a–e (0.33 mmol) in
CHCl3 (40 mL), tin(powder) (3.3 g), and HCl (37%, w/v;
11 mL) were added, and the reaction mixture was stirred
vigorously for 1 h at r.t. After this period, the reaction
mixture was neutralized with NaHCO3, filtered through
Celite, and the solid residue washed with H2O and CHCl3.
The filtrate was extracted with CHCl3, the organic layer was
dried over Na2SO4, filtered, and evaporated to dryness. The
mixture was purified by silica gel column chromatography,
eluting with CH2Cl2, giving 3-aminoflavones (for yield, see
Table 2).
(29) Physical Data for 3-Nitro-4¢-trifluoroacetamidoflavone
(1e)
Mp 228–230 °C. 1H NMR (300 MHz, DMSO-d6): d = 7.65
(ddd, 1 H, J = 8.1, 7.0, 1.0 Hz, H-6), 7.84 (d, 2 H, J = 8.8 Hz,
H-3¢,5¢), 7.86 (d, 1 H, J = 8.4 Hz, H-8), 7.95 (d, 2 H, J = 8.8
Hz, H-2¢,6¢), 7.98 (ddd, 2 H, J = 8.4, 7.0, 1.6 Hz, H-7), 8.19
(dd, 1 H, J = 8.1, 1.6 Hz, H-5), 11.69 (s, 1 H, 4¢-NHCOCF3)
ppm. 13C NMR (75.47 MHz, DMSO-d6): d = 115.6 (Cq,
J = 288.6 Hz, 4¢-NHCOCF3), 119.2 (C-8), 121.3 (C-3¢,5¢),
122.8 (C-10), 124.9 (C-5), 125.5 (C-6), 126.9 (C-1¢), 129.2
(C-2¢,6¢), 136.0 (C-7), 137.5 (C-3), 140.5 (C-4¢), 155.0 (Cq,
J = 37.0 Hz, 4¢-NHCOCF3), 155.2 (C-9), 159.4 (C-2), 168.5
(C-4) ppm. 19F NMR (282.40 MHz, DMSO-d6): d = –97.46
(4¢-NHCOCF3) ppm. ESI-MS (+): m/z (%) = 417 (22) [M +
K]+, 401 (100) [M + Na]+, 379 (88) [M + H]+. Anal. Calcd
for C17H9F3N2O5: C, 53.96; H, 2.40; N, 7.41. Found: C,
54.02; H, 2.26; N, 7.25.
(35) (a) Ram, S.; Ehrenkaufer, R. E. Synthesis 1986, 133.
(b) Haldar, P.; Mahajani, V. V. Chem. Eng. J. 2004, 104, 27.
(c) Byun, E.; Hong, B.; De Castro, K. A.; Kim, M.; Rhee, H.
J. Org. Chem. 2007, 72, 9815.
(36) Physical Data for 3-Amino-4¢-trifluoroacetamido-
flavone (8e)
Mp 195–196 °C. 1H NMR (300 MHz, DMSO-d6): d = 4.80
(s, 2 H, 3-NH2), 7.43 (ddd, 1 H, J = 8.1, 6.9, 1.2 Hz, H-6),
7.67 (ddd, 1 H, J = 8.6, 1.2, 0.5 Hz, H-8), 7.76 (ddd, 1 H,
J = 8.6, 6.9, 1.7 Hz, H-7), 8.04 (d, 2 H, J = 9.0 Hz, H-3¢,5¢),
7.89 (d, 2 H, J = 9.1 Hz, H-2¢,6¢), 8.10 (ddd, 1 H, J = 8.1, 1.7,
0.5 Hz, H-5), 11.51 (s, 1 H, 4¢-NHCOCF3) ppm. 13C NMR
(125.67 MHz, DMSO-d6): d = 115.8 (quart, J = 288.6 Hz, 4¢-
NHCOCF3), 118.3 (C-8), 120.1 (C-10), 121.0 (C-2¢,6¢),
124.3 (C-6), 125.0 (C-5), 128.2 (C-3¢,5¢), 128.6 (C-3), 129.6
(C-1¢), 133.3 (C-7), 137.2 (C-4¢), 142.3 (C-2), 154.7 (quart,
J = 37.1 Hz, 4¢NHCOCF3), 154.7 (C-9), 172.7 (C-4) ppm.
19F NMR (282.40 MHz, DMSO-d6): d = –97.36 (s, 4¢-
NHCOCF3) ppm. ESI-MS (+): m/z (%) = 371 (21) [M +
Na]+, 349 (100) [M + 1]+. Anal. Calcd for C17H11F3N2O3: C,
58.63; H, 3.18; N, 8.04. Found: C, 58.42; H, 3.49; N, 7.85.
(30) Physical Data for 4¢-Trifluoroacetamidoflavone (7e)
Mp 280–282 °C. 1H NMR (300 MHz, DMSO-d6): d = 7.05
(s, 1 H, H-3), 7.51 (ddd, 1 H, J = 8.1, 6.9, 1.4 Hz, H-6), 7.79
(dd, 1 H, J = 8.4, 1.0 Hz, H-8), 7.85 (ddd, 1 H, J = 8.4, 6.8,
1.6 Hz, H-7), 7.90 (d, 2 H, J = 8.9 Hz, H-3¢,5¢), 8.06 (dd, 1
H, J = 7.9, 1.4 Hz, H-5), 8.18 (d, 2 H, J = 8.9 Hz, H-2¢,6¢),
11.60 (s, 1 H, 4¢-NHCOCF3) ppm. 13C NMR (75.47 MHz,
Synlett 2010, No. 9, 1381–1385 © Thieme Stuttgart · New York