A Novel and Efficient Route for the Synthesis of Hydroxylated 2,3-Diarylxanthones

Abstract

A novel, efficient and general route for the synthesis of hydroxylated 2,3-diarylxanthones is described. 3-Bromo-2-styrylchromone, the key intermediate of this synthesis, is obtained by a Baker-Venkataraman rearrangement of the appropriate 2′-cinnamoyloxyacetophenone, followed by a one-pot reaction with phen­yltrimethylammonium tribromide. The Heck reaction of these bromochromones with substituted styrenes gives methoxylated 2,3-diarylxanthones. The cleavage of the methyl groups with BBr₃ gives the desired hydroxylated 2,3-diarylxanthones.

Key words

hydroxylated diarylxanthones - 3-bromo-2-styrylchromones - phenyltrimethylammonium tribromide - Heck reaction - demethylation

References and Notes

• 1a Hostettman K. Hostettman M. In Methods in Plant Biochemistry, Plant Phenolics   Vol. 1:  Dey PM. Harbone JB. Academic Press; London: 1989.  p.493 
• 1b Bennett GJ. Lee H.-H. Phytochemistry  1989,  28:  967 
• 1c Gales L. Damas AM. Curr. Med. Chem.  2005,  12:  2499 
• 2a Vieira LMM. Kijjoa A. Curr. Med. Chem.  2005,  12:  2413 
• 2b Roberts JC. Chem. Rev.  1961,  591 
• 3 Pinto MMM. Sousa ME. Nascimento MSJ. Curr. Med. Chem.  2005,  12:  2517 
• 4a Dube M. Zunker K. Neidhart S. Carle R. Steinhart H. Paschke A. J. Agric. Food Chem.  2004,  52:  3938 
• 4b Pfister JR. Ferraresi RW. Harrison IT. Rooks WH. Freid JH. J. Med. Chem.  1978,  21:  669 
• 5a Abdel-Lateff A. Klemke C. König GM. Wright AD. J. Nat. Prod.  2003,  66:  706 
• 5b Fukai T. Yonekawa M. Hou A.-J. Nomura T. Sun H.-D. Uno J. J. Nat. Prod.  2003,  66:  1118 
• 5c Mackeen MM. Ali AM. Lajis NH. Kawazu K. Hassan Z. Amran M. Habsah M. Mooi LY. Mohamed SM. J. Ethanopharmacol.  2000,  72:  395 
• 6a 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 
• 6b Lin CN. Chung MI. Liou SJ. Lee TH. Wang JP. J. Pharm. Pharmacol.  1996,  48:  532 
• 7a Riscoe M. Kelly JX. Winter R. Curr. Med. Chem.  2005,  12:  2539 
• 7b Portela C. Afonso CMM. Pinto MMM. Ramos MJ. Bioorg. Med. Chem.  2004,  12:  3313 
• 7c Dua VK. Ojha VP. Roy R. Joshi BC. Valecha N. Devi CU. Batnagar MC. Sharma VP. Subbarao SK. J. Ethanopharmacol.  2004,  95:  247 
• 8a Zhang H.-Z. Kasibhatla S. Wang Y. Herich J. Guastella J. Tseng B. Drewe J. Cai SX. Bioog. Med. Chem.  2004,  12:  309 
• 8b Rewcastle GW. Atwell GJ. Zhang L. Baguley BC. Denny WA. J. Med. Chem.  1991,  34:  217 
• 9a Merza J. Aumond M.-C. Rondeau D. Dumontet V. Le Ray A.-M. Séraphin D. Richomme P. Phytochemistry  2004,  65:  2915 
• 9b Hay A.-E. Aumond M.-C. Mallet S. Dumontet V. Litaudon M. Rondeau D. Richomme P. J. Nat. Prod.  2004,  67:  707 
• 9c Pauletti PM. Castro-Gamboa I. Silva DHS. Young MCM. Tomazela DM. Eberlin MN. Bolzani VS. J. Nat. Prod.  2003,  66:  1384 
• 10a Park KH. 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 
• 10b Lee BW. Lee JH. Lee S.-T. Lee HS. Lee WS. Jeong T.-S. Park WS. Bioorg. Med. Chem. Lett.  2005,  15:  5548 
• 11a Garrity AR, Morton GAR, and Morton JC. inventors; US Patent,  6730333. 
• 11b Sellés AJN. Castro HTV. Agüero-Agüero J. González-González J. Naddeo F. De Simone F. Rastrelli L. J. Agric. Food Chem.  2002,  50:  762 
• 12 Sousa ME. Pinto MMM. Curr. Med. Chem.  2005,  12:  2447 
• 13 Santos CMM. Silva AMS. Cavaleiro JAS. Synlett  2005,  3095 
• 14a Mahal HS. Venkataraman K. J. Chem. Soc.  1934,  1767 
• 14b Baker W. J. Chem. Soc.  1933,  1381 
• 17 Fougerousse A. Gonzalez E. Brouillard R. J. Org. Chem.  2000,  65:  583 
• 18a Trzeciak AM. Ziókoeski JJ. Coord. Chem. Rev.  2007,  251:  1281 
• 18b Nicolaou KC. Bulger PG. Sarlah D. Angew. Chem. Int. Ed.  2005,  44:  4442 
• 18c Farina V. Adv. Synth. Catal.  2004,  346:  1553 
• 22a Punna S. Meunier UH. Finn MG. Org. Lett.  2004,  6:  2777 
• 22b Nordvik T. Brinker UH. J. Org. Chem.  2003,  68:  9394 

15

Typical Experimental Procedure: Phenyltrimethylammonium tribromide (PTT; 2.1 g, 5.5 mmol) was added to a THF (60 mL) solution of the appropriate 5-aryl-3-hydroxy-1-(2-hydroxyphenyl)-2,4-pentadien-1-ones 4a-c (5 mmol). The reaction mixture was stirred and allowed to stand at r.t. for 12 h. After that period, the solution was poured into ice (50 g) and H₂O (80 mL), stirred for 20 min and the yellow solid was removed by filtration. The residue was taken in CHCl₃ (50 mL) and washed with H₂O (3 × 50 mL). The organic layer was collected, the solvent was evaporated to dryness and the residue was purified by silica gel column chromatography using CH₂Cl₂ as eluent. The solvent was evaporated and the residue was recrystallized from EtOH to give the 3-bromo-2-styrylchromones 5a-c in good yields (5a: 67%; 5b: 53%; 5c: 64%).

16

Physical Data of 3-Bromo-3′,4′-dimethoxy-2-styryl-chromone (5c): mp 187-189 ºC. ¹H NMR (300.13 MHz, CDCl₃): δ = 3.95 (s, 3 H, 4′-OMe), 3.98 (s, 3 H, 3′-OMe), 6.92 (d, J = 8.3 Hz, 1 H, H-5′), 7.14 (d, J = 2.0 Hz, 1 H, H-2′), 7.24 (dd, J = 2.0, 8.3 Hz, 1 H, H-6′), 7.33 (d, J = 15.8 Hz, 1 H, H-α), 7.41 (ddd, J = 0.8, 7.7, 7.8 Hz, 1 H, H-6), 7.53 (d, J = 7.9 Hz, 1 H, H-8), 7.66 (d, J = 15.8 Hz, 1 H, H-β), 7.70 (ddd, J = 1.6, 7.7, 7.9 Hz, 1 H, H-7), 8.23 (dd, J = 1.6, 7.8 Hz, 1 H, H-5). ¹³C NMR (75.47 MHz, CDCl₃): δ = 55.96, 55.99 (3′-OMe, 4′-OMe), 109.0 (C-3), 109.6 (C-2′), 111.1 (C-5′), 116.9 (C-α), 117.4 (C-8), 122.1 (C-10), 122.6 (C-6′), 125.3 (C-6), 126.4 (C-5), 127.9 (C-1′), 133.9 (C-7), 139.6 (C-β), 149.3 (C-3′), 151.2 (C-4′), 154.9 (C-9), 158.7 (C-2), 172.7 (C-4). MS (ESI⁺): m/z (%) = 387 (19) ([M + H]⁺, ⁷⁹Br), 389 (20) ([M + H]⁺, ⁸¹Br), 409 (9) ([M + Na]⁺, ⁷⁹Br), 411 (9) ([M + Na]⁺, ⁸¹Br), 425 (4) ([M + K]⁺, ⁷⁹Br), 427 (4) ([M + K]⁺, ⁸¹Br), 795 (7) ([2 × M + Na]⁺, ⁷⁹Br), 797 (15) ([2 × M + Na]⁺, ⁸¹Br). Anal. Calcd for C₁₉H₁₅BrO₄: C, 58.93; H, 3.90. Found: C, 58.53; H, 3.84.

19

Typical Experimental Procedure: To a mixture of the appropriate 3-bromo-2-styrylchromones 5a-c (0.4 mmol), triphenylphosphine (10.5 mg, 0.04 mmol), tetrakis(triphenylphosphine)palladium(0) (23.1 mg, 0.02 mmol) and triethylamine (55.8 µL, 0.4 mmol) in N-methyl-2-pyrrolidinone (6 mL) was added the appropriate styrene 6a-c (2 mmol for styrene 6a and 0.8 mmol for styrenes 6b,c). The reaction mixture was stirred under different conditions of time and temperature according to the substituents in the compounds (Table [1] ). Then, the mixture was poured into H₂O (20 mL) and ice (10 g) and extracted with Et₂O (4 × 25 mL) and dried over anhyd Na₂SO₄. The residue was evaporated, taken in CH₂Cl₂ (15 mL) and purified by TLC (eluent: CH₂Cl₂-light petroleum, 7:3). Two spots were collected in each case: the major one, having higher R _f value, consisted of 2,3-diarylxanthones 7a-i and the minor one, with lower R _f value, consisted of 2,3-diaryl-3,4-dihydroxanthones 8a-i. The 2,3-diarylxanthones 7a-i were recrystallized from EtOH in yields presented in Table [1] .

20

Physical Data of 2-(4-Methoxyphenyl)-3-(3,4-dimeth­-oxyphenyl)xanthone (7h): mp 148-150 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 3.60 (s, 3 H, 4′′-OMe), 3.80 (s, 3 H, 4′-OMe), 3.90 (s, 3 H, 3′′-OMe), 6.61 (d, J = 2.0 Hz, 1 H, H-2′′), 6.81 (d, J = 8.8 Hz, 2 H, H-3′, H-5′), 6.83 (d, J = 8.0 Hz, 1 H, H-5′′), 6.90 (dd, J = 2.0, 8.0 Hz, 1 H, H-6′′), 7.11 (d, J = 8.8 Hz, 2 H, H-2′, H-6′), 7.40 (ddd, J = 0.9, 7.7, 7.8 Hz, 1 H, H-7), 7.52 (dd, J = 0.9, 8.1 Hz, 1 H, H-5), 7.56 (s, 1 H, H-4), 7.75 (ddd, J = 1.7, 7.7, 8.1 Hz, 1 H, H-6), 8.33 (s, 1 H, H-1), 8.37 (dd, J = 1.7, 7.8 Hz, 1 H, H-8). ¹³C NMR (75.47 MHz, CDCl₃): δ = 55.2 (4′-OMe), 55.6 (4′′-OMe), 55.8 (3′′-OMe), 110.7 (C-5′′), 113.2 (C-2′′), 113.6 (C-3′, C-5′), 118.0 (C-5), 119.0 (C-4), 120.4 (C-9a), 121.9 (C-8a, C-6′), 123.9 (C-7), 126.7 (C-8), 128.1 (C-1), 130.9 (C-2′, C-6′), 132.4, 132.5 (C-1′, C-1′′), 134.7 (C-6), 136.6 (C-2), 147.3 (C-3), 148.2, 148.5 (C-3′′, C-4′′), 155.1 (C-4a), 156.3 (C-4b), 158.6 (C-4′), 177.0 (C-9). MS (EI): m/z (%) = 438 (100) [M⁺·], 423 (11), 407 (14), 380 (8), 363 (8), 309 (8), 308 (31), 307 (25), 293 (14), 292 (12), 291 (12), 277 (10), 250 (7), 222 (6), 188 (24), 151 (8), 102 (9), 86 (8), 84 (11). Anal. Calcd for C₂₈H₂₂O₅: C, 76.70, H, 5.06. Found: C, 76.41; H, 5.42.

21

Physical Data of 2-(4-Methoxyphenyl)-3-(3,4-dimeth­-oxyphenyl)-3,4-dihydroxanthone (8h): yellow oil. ¹H NMR (300.13 MHz, CDCl₃): δ = 2.98 (dd, J = 1.3, 17.2 Hz, 1 H, H-4 _trans ), 3.62 (dd, J = 8.8, 17.2 Hz, 1 H, H-4 _cis ), 3.76 (s, 3 H, 3′′-OMe), 3.79 (s, 6 H, 4′-OMe, 4′′-OMe), 4.22 (dd, J = 1.3, 8.8 Hz, 1 H, H-3), 6.71 (d, J = 8.1 Hz, 1 H, H-5′′), 6.81-6.86 (m, 2 H, H-2′′, H-6′′), 6.83 (d, J = 8.9 Hz, 2 H, H-3′, H-5′), 7.36 (d, J = 8.0 Hz, 2 H, H-5), 7.38 (ddd, J = 1.4, 7.6, 7.7 Hz, 1 H, H-7), 7.44 (s, 1 H, H-1), 7.44 (d, J = 8.9 Hz, 2 H, H-2′, H-6′), 7.60 (ddd, J = 1.6, 7.7, 8.0 Hz, 1 H, H-6), 8.28 (dd, J = 1.6, 7.6 Hz, 1 H, H-8). ¹³C NMR (75.47 MHz, CDCl₃): δ = 36.8 (C-4), 41.4 (C-3), 55.3, 55.75, 55.80 (4′-OMe, 3′′-OMe, 4′′-OMe), 110.4 (C-2′′), 111.4 (C-5′′), 113.9 (C-3′, C-5′), 114.8 (C-1), 116.9 (C-9a), 118.0 (C-5), 119.2 (C-6′′), 123.8 (C-8a), 125.0 (C-7), 126.2 (C-8), 126.9 (C-2′, C-6′), 131.7 (C-1′), 132.9 (C-6), 133.1 (C-1′′), 135.3 (C-2), 148.0 (C-4′′), 149.1 (C-3′′), 155.9 (C-4b), 159.2 (C-4′), 162.2 (C-4a), 174.2 (C-9). MS (EI): m/z (%) = 440 (13) [M⁺·], 439 (26), 438 (100), 423 (13), 497 (14), 391 (7), 380 (7), 363 (7). HRMS (EI): m/z calcd for C₂₈H₂₄O₅: 440.1624; found: 440.1624.

23

Typical Experimental Procedure: A solution of the appropriate 2,3-diarylxanthones 7b-i in freshly distilled CH₂Cl₂ (3 mL) was cooled to - 78 °C under nitrogen. A solution of BBr₃ in 0.1 M CH₂Cl₂ (2.5 equiv for each methyl group to be cleaved) was gradually added. The reaction mixture was stirred at r.t. for a period of time according to the substituents in the compounds (1 h for each group to be cleaved). After that period, the solution was poured into H₂O (20 mL) and vigorously stirred until the formation of a yellow precipitate. The solid was washed abundantly with H₂O (4 × 50 mL) and then with light petroleum (4 × 20 mL) to afford the hydroxylated 2,3-diarylxanthones 9b-i in good yields (9b: 72%; 9c: 80%; 9d: 82%; 9e: 94%; 9f: 80%; 9g: 80%; 9h: 94%; 9i: 70%).

24

Physical Data of 2-(4-Hydroxyphenyl)-3-(3,4-dihy­-droxyphenyl)xanthone (9h): mp 277-279 °C. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 6.50 (dd, J = 2.0, 8.1 Hz, 1 H, H-6′′), 6.62 (d, J = 2.0 Hz, 1 H, H-2′′), 6.67 (d, J = 8.1 Hz, 1 H, H-5′′), 6.70 (d, J = 8.4 Hz, 2 H, H-3′, H-5′), 6.99 (d, J = 8.4 Hz, 2 H, H-2′, H-6′), 7.50 (dd, J = 7.6, 7.7 Hz, 1 H, H-7), 7.52 (s, 1 H, H-4), 7.68 (d, J = 8.1 Hz, 1 H, H-5), 7.89 (ddd, J = 1.5, 7.6, 8.1 Hz, 1 H, H-6), 8.01 (s, 1 H, H-1), 8.22 (dd, J = 1.5, 7.7 Hz, 1 H, H-8), 8.97 (s, 1 H, 4′′-OH), 9.15 (s, 1 H, 3′′-OH), 9.51 (s, 1 H, 4′-OH). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 115.1 (C-3′, C-5′), 115.5 (C-5′′), 116.9 (C-2′′), 118.3 (C-5), 118.9 (C-4), 119.6 (C-9a), 120.8 (C-6′′), 121.3 (C-8a), 124.4 (C-7), 126.1 (C-8), 127.0 (C-1), 130.5 (C-1′, C-2′, C-6′), 130.7 (C-1′′), 135.5 (C-6), 136.6 (C-2), 145.0 (C-3′′), 145.3 (C-4′′), 147.7 (C-3), 154.4 (C-4a), 155.8 (C-4b), 156.4 (C-4′), 175.7 (C-9). MS (EI): m/z (%) = 396 (100) [M⁺·], 395 (6), 380 (7), 379 (11), 349 (8), 98 (10), 97 (10), 83 (10). HRMS (EI): m/z calcd for C₂₅H₁₆O₅: 396.0998; found: 396.0996.