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Synlett 2010(9): 1381-1385  
DOI: 10.1055/s-0029-1219838
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Regioselective 3-Nitration of Flavones: A New Synthesis of 3-Nitro- and 3-Aminoflavones

Diana T. Patoilo, Artur M. S. Silva*, José A. S. Cavaleiro
Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
Fax: +351(234)370084; e-Mail: artur.silva@ua.pt;
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Publication History

Received 1 March 2010
Publication Date:
16 April 2010 (online)

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Abstract

A new, general, and regioselective method for the 3-nitration of flavones have been developed. The nitration reaction is solvent dependent, proceeds via a nitro radical pathway, and the corresponding 3-nitroflavones have been obtained in moderate to very good yields (up to 81%). The reduction of 3-nitroflavones allowed the preparation of the corresponding 3-aminoflavones in very good yields (up to 96%).

Key words

flavones - nitration - regioselectivity - reduction - radical reaction

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General Procedure for the Nitration of Flavones 1a-e: Synthesis of 3-Nitroflavones 2a-e
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] ).

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Physical Data for 3-Nitro-4′-trifluoroacetamidoflavone (1e)
Mp 228-230 ˚C. ¹H NMR (300 MHz, DMSO-d 6): δ = 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-d 6): δ = 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-d 6): δ = -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.

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Physical Data for 4′-Trifluoroacetamidoflavone (7e)
Mp 280-282 ˚C. ¹H NMR (300 MHz, DMSO-d 6): δ = 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, DMSO-d 6): δ = 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-d 6): δ = -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.

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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] ).

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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] ).

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Physical Data for 3-Amino-4′-trifluoroacetamido-flavone (8e)
Mp 195-196 ˚C. ¹H NMR (300 MHz, DMSO-d 6): δ = 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-d 6): δ = 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-d 6): δ = -97.36 (s, 4′-NHCOCF 3) 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.