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

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%).

flavones - nitration - regioselectivity - reduction - radical reaction

References and Notes

<A NAME="RD05810ST-1A">1a</A> The Flavonoids - Advances in Research Since 1986   Harborne JB. Chapman and Hall; London: 1994. 

<A NAME="RD05810ST-1B">1b</A> Harborne JB. Williams CA. Phytochemistry  2000,  55:  481 

<A NAME="RD05810ST-2A">2a</A> Flavonoids in Health and Disease   Rice-Evans C. Packer L. Marcel Dekker; New York: 1998. 

<A NAME="RD05810ST-2B">2b</A> Middleton E. Kandaswami C. Theoharides TC. Pharmacol. Rev.  2000,  52:  673 

<A NAME="RD05810ST-2C">2c</A> Silva AMS. Pinto DCGA. Cavaleiro JAS. In Targets in Heterocyclic Systems - Chemistry and Properties   Vol. 4:  Attanasi OA. Spinelli D. Italian Society of Chemistry; Rome: 2001.  p.231 

<A NAME="RD05810ST-2D">2d</A> Rice-Evans C. Curr. Med. Chem.  2001,  8:  797 

<A NAME="RD05810ST-2E">2e</A> Manthey JA. Guthrie N. Grohmann K. Curr. Med. Chem.  2001,  8:  135 

<A NAME="RD05810ST-3A">3a</A> Marder M. Viola H. Wasowski C. Wolfman C. Waterman PG. Medina JH. Paladini AC. Bioorg. Med. Chem. Lett.  1995,  5:  2717 

<A NAME="RD05810ST-3B">3b</A> Viola H. Marder M. Wolfman C. Wasowski C. Medina JH. Paladini AC. Bioorg. Med. Chem. Lett.  1997,  7:  373 

<A NAME="RD05810ST-4">4</A> Wolfman C. Viola H. Marder M. Wasowski C. Ardenghi P. Izquierdo I. Paladini AC. Medina JH. Eur. J. Pharmacol. Lett.  1995,  5:  2717 

<A NAME="RD05810ST-5">5</A> Davis JW. Burdick AD. Lauer FT. Burchiel SW. Toxicol. Appl. Pharmacol.  2003,  188:  42 

<A NAME="RD05810ST-6">6</A> Bauvois B. Puiffe M.-L. Bongui J.-B. Paillat S. Monneret C. Dauzonne D. J. Med. Chem.  2003,  46:  3900 

<A NAME="RD05810ST-7">7</A> Akama T. Ishida H. Kimura U. Gomi K. Saito H.
J. Med. Chem.  1998,  41:  2056 

<A NAME="RD05810ST-8">8</A> Cushman M. Zhu H. Geahlen RL. Kraker AJ. J. Med. Chem.  1994,  37:  3353 

<A NAME="RD05810ST-9">9</A> Gao H. Kawabata J. Bioorg. Med. Chem.  2005,  13:  1661 

<A NAME="RD05810ST-10">10</A> Beudot C. De Méo MP. Dauzonne D. Elias R. Laget M. Guiraud H. Balansard G. Duménil G. Mutation Res.  1998,  417:  141 

<A NAME="RD05810ST-11">11</A> Steele VE. Boone CW. Dauzonne D. Rao CV. Bensasson RV. Cancer Res.  2002,  62:  6506 

<A NAME="RD05810ST-12">12</A> Dauzonne D. Folléas B. Martinez L. Chabot GG. Eur. J. Med. Chem.  1997,  71 

<A NAME="RD05810ST-13">13</A> Tang L. Zhang S. Yang J. Gao W. Cui J. Zhuang T. Synth. Commun.  2005,  35:  315 

<A NAME="RD05810ST-14">14</A> Marder M. Viola H. Bacigaluppo JA. Colombo MI. Wasowski C. Wolfman C. Medina JH. Rúveda JH. Paladini AC. Biochem. Biophys. Res. Commun.  1998,  249:  481 

<A NAME="RD05810ST-15">15</A> Anand N. Venkataraman FA. Proc. Indian Acad. Sci. A  1947,  26:  279 

<A NAME="RD05810ST-16">16</A> Barros AIRNA. Silva AMS. Monatsh. Chem.  2006,  137:  1505 

<A NAME="RD05810ST-17A">17a</A> Michalska M. Chem. Ind. (London)  1966,  628 

<A NAME="RD05810ST-17B">17b</A> Michalska M. Bull. Acad. Pol. Sci., Ser. Sci. Chem.  1968,  16:  567 

<A NAME="RD05810ST-18">18</A> Paparao C. Rao KV. Sundaramurthy V. Synthesis  1981,  236 

<A NAME="RD05810ST-19A">19a</A> Dauzonne D. Demerseman P. Synthesis  1990,  66 

<A NAME="RD05810ST-19B">19b</A> Dauzonne D. Grandjean C. Synthesis  1992,  677 

<A NAME="RD05810ST-20">20</A> Dauzonne D. Martinez L. Tetrahedron Lett.  1995,  36:  1845 

<A NAME="RD05810ST-21A">21a</A> Barros AIRNA. Silva AMS. Magn. Reson. Chem.  2006,  44:  1122 

<A NAME="RD05810ST-21B">21b</A> Barros AIRNA. Dias AFR. Silva AMS. Monatsh. Chem.  2007,  138:  585 

<A NAME="RD05810ST-22">22</A> Deng B.-L. Lepoivre JA. Lumière G. Eur. J. Org. Chem.  1999,  2683 

<A NAME="RD05810ST-23">23</A> Takechi A. Takikawa H. Miyake H. Sasaki M. Chem. Lett.  2006,  35:  128 

<A NAME="RD05810ST-24A">24a</A> Olah GA. Malhorta R. Narang SC. Nitration - Methods and Mechanism   VCH; New York: 1989. 

<A NAME="RD05810ST-24B">24b</A> Ono N. The Nitro Group in Organic Synthesis   Wiley-VCH; New York: 2001. 

<A NAME="RD05810ST-25A">25a</A> Salzbrunn S. Simon J. Prakash GKR. Petasis NA. Olah GA. Synlett  2000,  1485 

<A NAME="RD05810ST-25B">25b</A> Prakash GKR. Panja C. Mathew T. Surampudi V. Petasis NA. Olah GA. Org. Lett.  2004,  6:  2205 

<A NAME="RD05810ST-25C">25c</A> Deghati PYF. Bieraugel H. Wanner MJ. Koomen GJ. Tetrahedron Lett.  2000,  41:  569 

<A NAME="RD05810ST-25D">25d</A> Mellor JM. Mittoo S. Parkes R. Millar RW. Tetrahedron  2000,  8019 

<A NAME="RD05810ST-26">26</A> Crivello JV. J. Org. Chem.  1981,  46:  3056 

<A NAME="RD05810ST-27">27</A> Njoroge FG. Vibulbhan B. Pinto P. Chang T.-M. Osterman R. Remiszewski S. Del Rosario J. Doll R. Girijavallabhan V. Ganguly AK. J. Org. Chem.  1998,  63:  445 

<A NAME="RD05810ST-28">28</A>

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] ).

<A NAME="RD05810ST-29">29</A>

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 (C_q, 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 (C_q, 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.

<A NAME="RD05810ST-30">30</A>

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 (C_q, 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 (C_q, 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.

<A NAME="RD05810ST-31">31</A> Cunningham BD. Threadgill MD. Groundwater PW. Dale IL. Hickman JA. Anticancer Drug Des.  1992,  7:  365 

<A NAME="RD05810ST-32">32</A> Evans PA. Longmire JM. Tetrahedron Lett.  1994,  35:  8345 

<A NAME="RD05810ST-33">33</A>

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] ).

<A NAME="RD05810ST-34">34</A>

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] ).

<A NAME="RD05810ST-35A">35a</A> Ram S. Ehrenkaufer RE. Synthesis  1986,  133 

<A NAME="RD05810ST-35B">35b</A> Haldar P. Mahajani VV. Chem. Eng. J.  2004,  104:  27 

<A NAME="RD05810ST-35C">35c</A> Byun E. Hong B. De Castro KA. Kim M. Rhee H. J. Org. Chem.  2007,  72:  9815 

<A NAME="RD05810ST-36">36</A>

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.