A New Synthesis of 5-Arylbenzo[c]xanthones from Photoinduced Electrocyclisation
and Oxidation of (E)-3-Styrylflavones

Djenisa H. A. Rocha; Diana C. G. A. Pinto; Artur M. S. Silva; Tamás Patonay; José A. S. Cavaleiro

doi:10.1055/s-0031-1290355

LETTER

A New Synthesis of 5-Arylbenzo[c]xanthones from Photoinduced Electrocyclisation and Oxidation of (E)-3-Styrylflavones

Djenisa H. A. Rocha^a, Diana C. G. A. Pinto*^a, Artur M. S. Silva*^a, Tamás Patonay^b, José A. S. Cavaleiro^a
^a Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
Fax: +351(234)370084; e-Mail: artur.silva@ua.pt; e-Mail: diana@ua.pt;
^b Department of Organic Chemistry, University of Debrecen, 4010 Debrecen, Hungary

Abstract

All articles of this category

Abstract

A new synthetic route to 5-arylbenzo[c]xanthones is established. This was accomplished by use the Heck reaction of 3-bromoflavones with styrene derivatives, leading to (E)-3-styrylflavones with total diastereoselectivity. This transformation was greatly improved under microwave irradiation. The one-pot, photoinduced electrocyclisation of (E)-3-styrylflavones and further in situ oxidation of the cycloadduct leads to 5-arylbenzo[c]xanthones.

Key words

microwave irradiation - Heck reaction - photocyclisation - oxidation

Full Text

References

References and Notes

<A NAME="RD683ST-1A">1a</A> Roberts JC. Chem. Rev. 1961, 38: 591

<A NAME="RD683ST-1B">1b</A> Gales L. Damas AM. Curr. Med. Chem. 2005, 12: 2499

<A NAME="RD683ST-2">2</A> Park HH. Park Y.-D. Han J.-M. Im K.-R. Lee BW. Jeong IY. Jeong T.-S. Lee WS. Bioorg. Med. Chem. Lett. 2006, 16: 5580

<A NAME="RD683ST-3A">3a</A> Shadid KA. Shaari K. Abas F. Israf DA. Hamzah AS. Syakroni N. Saha K. Lajis NH. Phytochemistry 2007, 68: 2537

<A NAME="RD683ST-3B">3b</A> Ee GCL. Daud S. Izzaddin SA. Rahmani M. J. Asian Nat. Prod. Res. 2008, 10: 475

<A NAME="RD683ST-4">4</A> Suvarnakuta P. Chaweerungrat C. Devahastin S. Food Chem. 2011, 125: 240

<A NAME="RD683ST-5A">5a</A> Goyal S. Parthasarathy MR. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1992, 31: 391

<A NAME="RD683ST-5B">5b</A> Lokshin V. Heynderickx A. Samat A. Pèpe G. Guglielmetti R. Tetrahedron Lett. 1999, 40: 6761

<A NAME="RD683ST-5C">5c</A> Clarke DS. Gabbutt CD. Hepworth JD. Heron BM. Tetrahedron Lett. 2005, 46: 5515

<A NAME="RD683ST-5D">5d</A> Brito CM. Pinto DCGA. Silva AMS. Silva AMG. Tomé AC. Cavaleiro JAS. Eur. J. Org. Chem. 2006, 2558

<A NAME="RD683ST-5E">5e</A> Xu W.-Z. Huang Z.-T. Zheng Q.-T. J. Org. Chem. 2008, 73: 5606

<A NAME="RD683ST-6">6</A> Sonawane SA. Chavan VP. Shingare MS. Karale BK. Indian J. Heterocycl. Chem. 2002, 12: 65

<A NAME="RD683ST-7">7</A> Liu Y. Ma L. Chen W.-H. Wang B. Xu Z.-L. Bioorg. Med. Chem. 2007, 15: 2810

<A NAME="RD683ST-8">8</A> Sittisombut C. Boutefnouchet S. Van-Dufat HT. Tian W. Michel S. Koch M. Tillequin F. Pfeiffer B. Pierré A. Chem. Pharm. Bull. 2006, 54: 1113

<A NAME="RD683ST-9A">9a</A> Silva VLM. Silva AMS. Pinto DCGA. Cavaleiro JAS. Vasas A. Patonay T. Monatsh. Chem. 2008, 139: 1307

<A NAME="RD683ST-9B">9b</A> Patonay T. Vasas A. Kiss-Szikszai A. Silva AMS. Cavaleiro JAS. Austr. J. Chem. 2010, 63: 1592 ; and references cited therein

<A NAME="RD683ST-10">10</A> Sandulache A. Silva AMS. Cavaleiro JAS. Tetrahedron 2002, 58: 105

<A NAME="RD683ST-11A">11a</A> Heck RF. Nolley JP. J. Org. Chem. 1972, 37: 2330

<A NAME="RD683ST-11B">11b</A> Beletskaya IP. Cheprakov AV. Chem. Rev. 2000, 100: 3009

<A NAME="RD683ST-12A">12a</A> Santos CMM. Silva AMS. Cavaleiro JAS. Synlett 2007, 3113

<A NAME="RD683ST-12B">12b</A> Santos CMM. Silva AMS. Cavaleiro JAS. Eur. J. Org. Chem. 2009, 2642

<A NAME="RD683ST-13">13</A> Hoffmann N. Chem. Rev. 2008, 108: 1052

Optimised procedure for the synthesis of 3-bromo-flavones 2a-f: Phenyltrimethylammonium tribromide (0.94 g, 2.45 mmol) was added to an anhydrous THF (30 mL) solution of the appropriate 3-aryl-1-(2-hydroxyphenyl)-propan-1,3-dione 1a-f (1.63 mmol). The reaction mixture was stirred at room temperature for 24-48 h. After that period, the reaction mixture was poured into a mixture of ice (10 g) and water (30 mL), stirred for 30 min, and extracted with chloroform (3 × 20 mL). The combined extracts were dried over sodium sulfate and evaporated to dryness. The obtained residue was purified by TLC (CH₂Cl₂-light petroleum, 9:1). After solvent evaporation, the obtained residue was recrystallised from ethanol giving 3-bromoflavones 2a-f [2a: 196 mg (40%); 2b: 226 mg (44%); 2c: 343 mg (45%); 2d: 230 mg (42%); 2e: 237 mg (42%); 2f: 188 mg (32%)]

3-Bromo-4-methylflavone(2b): Yellow solid; mp 146-148 ˚C. ^¹H NMR (300.13 MHz, CDCl₃): δ = 2.47 (s, 3 H, 4′-CH₃), 7.34 (d, J = 8.2 Hz, 2 H, H-3′,5′), 7.44 (br dd, J = 7.1, 8.3 Hz, 1 H, H-6), 7.51 (br d, J = 8.3 Hz, 1 H, H-8), 7.72 (ddd, J = 1.7, 7.1, 8.1 Hz, 1 H, H-7), 7.78 (d, J = 8.2 Hz, 2 H, H-2′,6′), 8.31 (dd, J = 1.7, 8.3 Hz, 1 H, H-5). ^¹³C NMR (75.47 MHz, CDCl₃): δ = 21.6 (4′-CH₃), 108.9 (C-3), 117.8 (C-8), 121.8 (C-10), 125.6 (C-6), 126.5 (C-5), 129.0 (C-3′,5′), 129.3 (C-2′,6′), 133.7 (C-1′), 134.1 (C-7), 141.7 (C-4′), 155.6 (C-9), 162.1 (C-2), 173.2 (C-4). MS (ESI⁺): m/z (%) = 315 (100) ([M + H]⁺, ⁷⁹Br), 317 (90) ([M + H]⁺, ^8¹Br), 337 (87) ([M + Na]⁺, ⁷⁹Br), 339 (83) ([M + Na]⁺, ^8¹Br). Anal. Calcd for C₁₆H₁₁O₂Br (315.16): C, 60.98; H, 3.52. Found: C, 60.88; H, 3.52

<A NAME="RD683ST-16">16</A> Joo YH. Kim JK. Synth. Commun. 1998, 28: 4287

<A NAME="RD683ST-17">17</A> Miyake H. Nishino S. Nishimura A. Sasaki M. Chem. Lett. 2007, 36: 522

<A NAME="RD683ST-18">18</A> Rinker B. Schnakenburg G. Nieger M. Waldvogel SR. Synthesis 2011, 0593

Rocha D. H. A., Pinto D. C. G. A., Silva A. M. S., Patonay T., Cavaleiro J. A. S.; unpublished results

<A NAME="RD683ST-20A">20a</A> Fitzmaurice RJ. Etheridge ZC. Jumel E. Woolfson DN. Caddick S. Chem. Commun. 2006, 4814

<A NAME="RD683ST-20B">20b</A> Polshettiwar V. Varma RS. Acc. Chem. Res. 2008, 41: 629

<A NAME="RD683ST-21A">21a</A> Kappe CO. Angew. Chem. Int. Ed. 2004, 43: 6250

<A NAME="RD683ST-21B">21b</A> Kappe CO. Dallinger D. Nat. Drug Discovery 2006, 5: 51

<A NAME="RD683ST-22A">22a</A> Jeffery T. Tetrahedron Lett. 1985, 26: 2667

<A NAME="RD683ST-22B">22b</A> Jeffery T. Synthesis 1987, 70

<A NAME="RD683ST-22C">22c</A> Woodcock S. Branchaud BP. Tetrahedron Lett. 2005, 46: 7213

<A NAME="RD683ST-22D">22d</A> Pan K. Noël S. Pinel C. Djakovitch L. J. Organomet. Chem. 2008, 693: 2863

Optimised procedure for the synthesis of 3-styryl-flavones 4a-g: A mixture of the appropriate 3-bromo-flavone 2a-f (0.296 mmol), anhydrous K₂CO₃ (123 mg, 0.888 mmol), tetrabutylammonium bromide (TBAB; 238 mg, 0.740 mmol), palladium acetate (9.97 mg, 0.044 mmol) and styrene 3a (0.170 mL, 1.48 mmol) in DMF (6 mL), was poured into a two-necked flask equipped with a magnetic stirring bar, fibre-optic temperature control, and reflux condenser and placed under a nitrogen atmosphere. The mixture was then irradiated in an Ethos SYNTH microwave (Milestone Inc.) at constant power of 300 W from 5-10 min. After that period, the reaction mixture was poured into a mixture of ice (1 g) and water (10 mL) and extracted with diethyl ether (3 × 10 mL). The organic layer was evaporated to dryness and the obtained residue was taken in ethyl acetate (10 mL) and washed with water (2 × 10 mL). The organic layer was dried with anhydrous sodium sulfate, evaporated and purified by column chromatography (CHCl₃-acetone, 9.6:0.4). After solvent evaporation, the obtained residue was recrystallised from ethanol to give 3-styrylflavones 4a-g [4a: 67 mg (70%); 4b: 68 mg (68%); 4c: 73 mg (70%); 4d: 66 mg (62%); 4e: 55 mg (50%); 4f: 51 mg (45%)]. The reaction of 3-bromoflavone 2a (0.296 mmol) with styrene 3b (1.48 mmol), under the same reaction conditions, yielded 3-(3,4-dimethoxystyryl)flavone 4g (72 mg, 63%)

( E )-3-(3,4-Dimethoxystyryl)flavone (4g): Yellow solid; mp 158-160 ˚C. ^¹H NMR (300.13 MHz, CDCl₃): δ = 3.86 (s, 3 H, 4′′-OCH₃), 3.88 (s, 3 H, 3′′-OCH₃), 6.72 (d, J = 16.2 Hz, 1 H, H-α), 6.82 (d, J = 8.1 Hz, 1 H, H-5′′), 6.93 (d, J = 1.6 Hz, 1 H, H-2′′), 6.95 (d, J = 9.2 Hz, 1 H, H-6′′), 7.44 (ddd, J = 1.7, 7.1, 8.3 Hz, 1 H, H-6), 7.51 (dd, J = 1.7, 8.3 Hz, 1 H, H-8), 7.53-7.58 (m, 3 H, H-3′,4′,5′), 7.69 (ddd, J = 1.7, 7.1, 8.3 Hz, 1 H, H-7), 7.76-7.79 (m, 2 H, H-2′,6′), 7.95 (d, J = 16.2 Hz, 1 H, H-β), 8.33 (dd, J = 1.7, 8.3 Hz, 1 H, H-5). ^¹³C NMR (75.47 MHz, CDCl₃): δ = 55.8 (4′′-OCH₃), 55.9 (3′′-OCH₃), 109.3 (C-2′′), 111.2 (C-5′′), 117.8 (C-3), 117.9 (C-8), 118.3 (C-α), 119.3 (C-6′′), 123.5 (C-10), 125.1 (C-6), 126.3 (C-5), 128.4 (C-3′,5′), 129.9 (C-2′,6′), 130.6 (C-4′), 131.3 (C-1′′), 133.3 (C-1′), 133.4 (C-7), 134.1 (C-β), 148.8 (C-3′′), 148.9 (C-4′′), 155.4 (C-9), 162.5 (C-2), 177.6 (C-4). MS (ESI⁺): m/z (%) = 385 (100) [M + H]⁺, 407 (20) [M + Na]⁺. Anal. Calcd for C₂₅H₂₀O₄ (384.42): C, 78.11; H, 5.24. Found: C, 78.15; H, 5.31

<A NAME="RD683ST-25">25</A> Silva VLM. Silva AMS. Cavaleiro JAS. Synlett 2010, 2565

<A NAME="RD683ST-26">26</A> Yamashita S. Bull. Chem. Soc. Jpn. 1961, 34: 487

5-Phenyl-7 H -benzo[ c ]xanthen-7-one (5a): Mp 197-198 ˚C. ^¹H NMR (300.13 MHz, CDCl₃): δ = 7.47 (br dd, J = 7.0, 8.0 Hz, 1 H, H-9), 7.47-7.50 (m, 1 H, H-4′), 7.52-7.54 (m, 4 H, H-2′,3′,5′,6′), 7.67 (ddd, J = 1.5, 6.2, 8.0 Hz, 1 H, H-3), 7.74 (ddd, J = 1.5, 6.2, 8.0 Hz, 1 H, H-2), 7.75 (br d, J = 8.0 Hz, 1 H, H-11), 7.81 (ddd, J = 1.3, 7.0, 8.0 Hz, 1 H, H-10), 8.02 (dd, J = 1.5, 8.0 Hz, 1 H, H-4), 8.24 (s, 1 H, H-6), 8.44 (dd, J = 1.3, 8.0 Hz, 1 H, H-8), 8.81 (dd, J = 1.5, 8.0 Hz, 1 H, H-1). ^¹³C NMR (75.47 MHz, CDCl₃): δ = 117.1 (C-6a), 118.1 (C-11), 121.9 (C-6), 122.5 (C-7a), 123.1 (C-1), 124.4 (C-12b), 124.5 (C-9), 126.6 (C-2), 126.7 (C-4), 126.8 (C-8), 127.6 (C-4′), 128.4 (C-2′,6′), 129.6 (C-3), 130.1 (C-3′,5′), 132.1 (C-10), 133.7 (C-4a), 134.4 (C-5), 136.6 (C-1′), 155.8 (C-12a), 168.4 (C-11a), 177.2 (C-7). MS (ESI⁺): m/z (%) = 323 (100) [M + H]⁺, 345 (22) [M + Na]⁺. MS (EI⁺): m/z calcd for C₂₃H₁₄O₂: 322.0994; found: 322.0995

5-Phenyl-5 H -benzo[ c ]xanthen-7(6 H )-one (6a): ^¹H NMR (300.13 MHz, CDCl₃): δ = 3.24 (dd, J = 9.0, 16.5 Hz, 1 H, H-6_cis), 3.33 (dd, J = 7.3, 16.5 Hz, 1 H, H-6_trans), 4.32 (dd, J = 7.3, 9.0 Hz, 1 H, H-5), 7.06 (dd, J = 7.6 Hz, 1 H, H-2), 7.18-7.23 (m, 2 H, H- 3′,5′), 7.23-7.26 (m, 1 H, H-4), 7.27-7.32 (m, 2 H, H-2′,6′), 7.38- 7.49 (m, 3 H, H-9,3,4′), 7.59 (dd, J = 1.4, 8.3 Hz, 1 H, H-11), 7.69 (ddd, J = 1.4, 7.0, 8.3 Hz, 1 H, H-10), 8.09 (dd, J = 1.8, 7.6 Hz, 1 H, H-1), 8.24 (dd, J = 1.4, 8.3 Hz, 1 H, H-8). ^¹³C NMR (75.47 MHz, CDCl₃): δ = 27.2 (C-6), 43.1 (C-5), 115.4 (C-6a), 117.9 (C-11), 123.6 (C-7a), 124.0 (C-1), 125.9 (C-8), 126.8 (C-4), 127.3 (C-4′), 128.2 (C-3′,5′), 128.47 (C-12b), 128.5 (C-2′,6′), 128.7 (C-2), 131.4 (C-3), 133.3 (C-10), 141.7 (C-1′), 142.7 (C-4a), 155.6 (C-11a), 157.4 (C-12a), 177.2 (C-7). MS (EI⁺): m/z calcd for C₂₃H₁₆O₂: 324.1150; found: 324.1147

Optimised procedure for the synthesis of 5-phenyl-7 H -benzo[ c ]xanthen-7-ones 5a-h: A mixture of the appropriate 3-styrylflavone 4a-g (0.15 mmol) and a catalytic amount of I₂ (10% mol) in 1,2,4-trichlorobenzene (20 mL), was poured into a three-necked flask equipped with a magnetic stirring bar, reflux condenser and a high-pressure mercury UV lamp with 400 W power. The mixture was then irradiated from 2 to 6 days. After that period, the reaction mixture was poured into a silica gel column and eluted with light petroleum to remove the excess of iodine and 1,2,4-trichlorobenzene. Upon changing the eluent to ethyl acetate-light petroleum (1:9 or 3:7), 5-phenyl-7H-benzo[c]xanthen-7-ones were obtained, which were recrystallised from ethanol 5a-h [5a: 50 mg (70%); 5b: 22 mg (45%); 5c: 50 mg (73%); 5d: 35 mg (74%); 5e: 15 mg (30%); 5f: 11 mg (20%); 5g: 23 mg (40%); 5h: 35 mg (60%)]

Physical data of 6-hydroxy-3-nitro-5-phenyl-7 H -benzo[ c ]xanthen-7-one (7e): ^¹H NMR (300.13 MHz, CDCl₃): δ = 7.46 (br d, J = 8.4 Hz, 2 H, H-3′,5′), 7.52-7.56 (m, 1 H, H-4′), 7.53-7.59 (m, 1 H, H-9), 7.56-7.62 (m, 2 H, H-2′,6′), 7.79 (br d, J = 8.3 Hz, 1 H, H-11), 7.93 (ddd, J = 1.4, 7.0, 8.3 Hz, 1 H, H-10), 8.20 (dd, J = 2.2, 9.2 Hz, 1 H, H-2), 8.41 (dd, J = 1.4, 8.3 Hz, 1 H, H-8), 8.51 (d, J = 2.2 Hz, 1 H, H-4), 8.77 (d, J = 9.2 Hz, 1 H, H-1), 12.71 (s, 1 H, 6-OH). ^¹³C NMR (75.47 MHz, CDCl₃): δ = 109.5 (C-6a), 116.9 (C-2), 118.2 (C-11), 119.5 (C-5), 120.3 (C-12b), 121.3 (C-7a), 121.4 (C-4), 125.0 (C-1), 125.5 (C-9), 126.2 (C-8), 128.3 (C-4′), 128.9 (C-2′,6′), 131.0 (C-3′,5′), 133.3 (C-1′), 136.1 (C-10), 136.6 (C-4a), 148.7 (C-3), 153.0 (C-12a), 154.3 (C-6), 155.7 (C-11a), 182.0 (C-7) ppm. MS (EI⁺): m/z calcd for C₂₃H₁₃O₅N 383.0794; found: 383.0791

<A NAME="RD683ST-31">31</A> Xu WZ. Huang ZT. Zheng QY. J. Org. Chem. 2008, 73: 5607

Physical data of 3,4-dimethoxy-5-phenyl-7 H -benzo[ c ]xanthen-7-one (5f): ^¹H NMR (300.13 MHz, CDCl₃): δ = 3.18 (s, 3 H, 4-OCH₃), 4.03 (s, 3 H, 3-OCH₃), 7.34-7.46 (m, 6 H, H-9,2′,3′,4′,5′,6′), 7.49 (d, J = 9.2 Hz, 1 H, H-2), 7.72 (d, J = 8.3 Hz, 1 H, H-11), 7.79 (ddd, J = 1.5, 7.0, 8.3 Hz, 1 H, H-10), 8.04 (s, 1 H, H-6), 8.41 (dd, J = 1.5, 8.3 Hz, 1 H, H-8), 8.60 (d, J = 9.2 Hz, 1 H, H-1). ^¹³C NMR (75.47 MHz, CDCl₃): δ = 56.4 (4-OCH₃), 60.6 (3-OCH₃), 110.1 (C-6a), 114.0 (C-2), 118.0 (C-11), 120.1 (C-1), 122.6 (C-7a), 124.4 (C-9), 124.8 (C-6), 126.3 (C-4′), 126.6 (C-8), 126.9 (C-2′,6′), 129.2 (C-3′,5′), 130.4 (C-4a), 130.8 (C-5), 134.2 (C-10), 141.4 (C-12a), 144.6 (C-4), 155.1 (C-3), 156.7 (C-11a), 178.9 (C-7). MS (EI⁺): m/z calcd for C₂₅H₁₈O₄: 382.1205; found: 382.1207

Physical data of 2,3-dimethoxy-5-phenyl-7 H -benzo[ c ]xanthen-7-one (5g): ^¹H NMR (300.13 MHz, CDCl₃): δ = 3.88 (s, 3 H, 3-OCH₃), 4.18 (s, 3 H, 2-OCH₃), 7.34 (s, 1 H, H-4), 7.45 (br dd, J = 7.0, 8.2 Hz, 1 H, H-9), 7.46-7.49 (m, 1 H, H-4′), 7.50-7.58 (m, 4 H, H-2′,3′,5′,6′), 7.75 (dd, J = 1.7, 8.2 Hz, 1 H, H-11), 7.79 (ddd, J = 1.7, 7.0, 8.2 Hz, 1 H, H-10), 8.01 (s, 1 H, H-1), 8.13 (s, 1 H, H-6), 8.45 (dd, J = 1.7, 8.2 Hz, 1 H, H-8). ^¹³C NMR (75.47 MHz, CDCl₃): δ = 55.9 (3-OCH₃), 56.2 (2-OCH₃), 102.0 (C-4), 105.9 (C-1), 116.4 (C-6a), 118.0 (C-11), 119.2 (C-12b), 120.7 (C-6), 122.4 (C-1′), 124.2 (C-9), 126.5 (C-7a), 126.7 (C-8), 127.6 (C-4′), 128.5 (C-2′,6′), 129.9 (C-3′,5′), 131.4 (C-4a), 134.1 (C-5), 135.3 (C-10), 139.9 (C-12a), 149.8 (C-2), 151.9 (C-3), 155.8 (C-11a), 176.9 (C-7). MS (EI⁺): m/z calcd for C₂₅H₁₈O₄: 382.1205; found: 382.1207