A Novel Short-Step Synthesis of New Xanthenedione Derivatives from the Cyclization of 3-Cinnamoyl-2-styrylchromones

Abstract

Novel (E)-3-aryl-4-benzylidene-8-hydroxy-3,4-dihydro-1H-xanthene-1,9(2H)-diones are prepared by the cyclization of (E,E)-3-cinnamoyl-5-hydroxy-2-styrylchromones efficiently catalyzed with boron tribromide. The (E,E)-3-cinnamoyl-5-hydroxy-2-styrylchromones are obtained from the Baker-Venkataraman rearrangement of (E,E)-2-acetyl-1,3-phenylene bis(3-phenylacrylate), which is greatly improved under microwave irradiation.

Key words

xanthenediones - 3-cinnamoyl-5-hydroxy-2-styrylchro­mones - microwave irradiation - cyclization - boron tribromide

References and Notes

• 1a Roberts JC. Chem. Rev.  1961,  38:  591 
• 1b Gales L. Damas AM. Curr. Med. Chem.  2005,  12:  2499 
• 2 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 
• 3a Shadid KA. Shaari K. Abas F. Israf DA. Hamzah AS. Syakroni N. Saha K. Lajis NHj. Phytochemistry  2007,  68:  2537 
• 3b Ee GCL. Daud S. Izzaddin SA. Rahmani M. J. Asian Nat. Prod. Res.  2008,  10:  475 
• 4 Suvarnakuta P. Chaweerungrat C. Devahastin S. Food Chem.  2011,  125:  240 
• 5 Chiang Y.-M. Kuo Y.-H. Oota S. Fukuyama Y. J. Nat. Prod.  2003,  66:  1070 
• 6 Azebaze AGB. Meyer M. Valentin A. Nguemfo EL. Fomum ZT. Nkengfack AE. Chem. Pharm. Bull.  2006,  54:  111 
• 7 An TY. Hu LH. Chen ZL. Chin. Chem. Lett.  2002,  13:  623 
• 8a Brito-Arias M. Tapia-Albarrán M. Padilla-Martínez I. Martínez-Martínez F. Espinosa G. Molins E. Espinosa E. J. Chem. Crystallogr.  1999,  29:  759 
• 8b Karthikeyan G. Pandurangan A. J. Mol. Catal. A: Chem.  2009,  311:  36 
• 8c Pore DM. Shaikh TS. Patil NG. Dongare SB. Desai UV. Synth. Commun.  2010,  40:  2215 
• 9 Gabbutt CD. Hepworth JD. Urquhart MWJ. Miguel LMV. J. Chem. Soc., Perkin Trans. 1  1997,  1819 
• 10a Gerwick WH. Lopez A. Van Duyne GD. Clardy J. Ortiz W. Baez A. Tetrahedron Lett.  1986,  27:  1979 
• 10b Gerwick WH. J. Nat. Prod.  1989,  52:  252 
• 11 Yoon JS. Lee MK. Sung SH. Kim YC. J. Nat. Prod.  2006,  69:  290 
• 12 Rocha-Pereira J. Cunha R. Pinto DCGA. Silva AMS. Nascimento MSJ. Bioorg. Med. Chem.  2010,  18:  4195 
• 13 Gomes A. Fernandes E. Silva AMS. Pinto DCGA. Santos CMM. Cavaleiro JAS. Lima JLFC. Biochem. Pharmacol.  2009,  78:  171 
• 14 Gomes A. Neuwirth O. Freitas M. Couto D. Ribeiro D. Figueiredo AGPR. Silva AMS. Seixas RSGR. Pinto DCGA. Tomé AC. Cavaleiro JAS. Fernandes E. Lima JLFC. Bioorg. Med. Chem.  2009,  17:  7218 
• 15 Gomes A. Fernandes E. Garcia MBQ. Silva AMS. Pinto DCGA. Santos CMM. Cavaleiro JAS. Lima JLFC. Bioorg. Med. Chem.  2008,  16:  7939 
• 16 Pinto DCGA. Silva AMS. Cavaleiro JAS. New J. Chem.  2000,  24:  85 
• 17 Königs P. Neumann O. Kataeva O. Schnakenburg G. Waldvogel S. Eur. J. Org. Chem.  2010,  6417 
• 18 Pinto DCGA. Silva AMS. Cavaleiro JAS. Synlett  2007,  1897 
• 24a Baker W. J. Chem. Soc.  1933,  1381 
• 24b Gualati KC. Venkataraman K. J. Chem. Soc.  1933,  942 
• 25 Bellur E. Langer P. J. Org. Chem.  2005,  70:  3819 

19

Optimized Experimental Procedure
A two-necked flask equipped with a magnetic stirring bar, fibre-optic temperature control, and reflux condenser was charged with a mixture of the appropriate (E,E)-2-acetyl-1,3-phenylene bis(3-phenylacrylate) 7a-g (1 mmol) and anhyd K₂CO₃ (28 mg, 2 mmol) in anhyd pyridine (10 mL) and was then irradiated in an Ethos SYNTH microwave (Milestone Inc.) at constant power of 400 W for 17 min. After this period the reaction mixture was poured onto a mixture of ice (10 g) and H₂O (20 mL), and the pH was adjusted to 2 with dilute HCl. The so-formed solids (E,E)-3-cinnamoyl-5-hydroxy-2-styrylchromones 8a-g were filtered off. In the case of compounds 8d and 8f a column chromatography purification, using CH₂Cl₂ as eluent, was necessary; 8a, 378 mg, 96%; 8b, 409 mg, 97%; 8c, 445 mg, 98%; 8d, 301 mg, 65%; 8e, 422 mg, 93%; 8f, 287 mg, 62%; 8g, 443 mg, 86%.

20

Physical Data of 5-Hydroxy-3′,4′-dimethoxy-3-(3,4-dimethoxycinnamoyl)-2-styrylchromone (8g)
Mp 208-211 ˚C. ^¹H NMR (300.13 MHz, CDCl₃): δ = 3.93 (s, 4 × 3 H, 3′,4′,3′′,4′′-OCH₃), 6.84 (dd, 1 H, J = 0.7, 8.2 Hz, H-6), 6.88 (d, 1 H, J = 8.3 Hz, H-5′′), 6.89 (d, 1 H, J = 8.3 Hz, H-5′), 6.90 (d, 1 H, J = 15.8 Hz, H-α), 7.02 (dd, 1 H, J = 0.7, 8.2 Hz, H-8), 7.07 (d, 1 H, J = 1.8 Hz, H-2′), 7.10 (d, 1 H, J = 15.8 Hz, H-α′), 7.13 (d, 1 H, J = 1.8 Hz,
H-2′′), 7.20 (dd, 2 H, J = 1.8, 8.3 Hz, H-6′,6′′), 7.59 (t, 1 H, J = 8.2 Hz, H-7), 7.62 (d, 1 H, J = 15.8 Hz, H-β′), 7.75 (d, 1 H, J = 15.8 Hz, H-β), 12.50 (s, 1 H, 5-OH) ppm. ^¹³C NMR (75.47 MHz, CDCl₃): δ = 56.0 (3′,4′,3′′,4′′-OCH₃), 106.7 (C-8), 109.9 and 110.1 (C-2′ and/or C-2′′), 110.5 (C-10), 111.0 and 111.1 (C-5′ and/or C-5′′), 111.8 (C-6), 115.1 (C-α), 120.3 (C-3), 123.1 (C-6′), 123.8 (C-6′′), 125.4 (C-α′), 127.3 (C-1′′), 127.8 (C-1′), 135.8 (C-7), 140.7 (C-β), 145.3 (C-β′), 149.2 and 149.3 (C-3′ and/or C-3′′), 151.5 and 151.7 (C-4′ and/or C-4′′), 155.4 (C-9), 161.0 (C-5), 162.6 (C-2), 181.6 (C-4), 190.9 (C=O) ppm. MS (ESI⁺): m/z (%) = 515 (60) [M + H]⁺, 537 (100) [M + Na]⁺, 553 (45) [M + K]⁺. HRMS (EI): m/z calcd for [C₃₀H₂₆O₈]⁺: 514.1628; found: 514.1639.

21

Optimized Experimental Procedure
A CH₂Cl₂ solution of BBr₃ (2 mmol) was slowly added to a solution of the appropriate (E,E)-3-cinnamoyl-5-hydroxy-2-styrylchromone 8a-g (0.4 mmol) in anhyd CH₂Cl₂ (20 mL) at low temperature (-78 ˚C). After the addition, the cooling system was removed, and the reaction mixture was stirred at r.t. for 3 h (8 h for 8d and 8f and 22 h for 8g). Then, H₂O
(80 mL) was added, and the resulting reaction mixture was stirred at r.t. for 3-4 h. The mixture was extracted with CHCl₃ (3 × 80 mL) and the combined extracts evaporated and purified by TLC, using CH₂Cl₂ as eluent (except in the case of compound 9g which was filtered off): 9a, 99 mg, 63%; 9b, 150 mg, 89%; 9c, 118 mg, 69%; 9d, 95 mg, 51%; 9e, 70 mg, 41%; 9f, 69 mg, 37%; 9g, 148 mg, 81%.

22

Physical Data of ( E )-8-Hydroxy-4-(4-hydroxy-benzylidene)-3-(4-hydroxyphenyl)-3,4-dihydro-1 H -xanthene-1,9 (2 H )-dione (9c)
Mp 319-320 ˚C. ^¹H NMR (300.13 MHz, DMSO-d ₆): δ = 2.69 (dd, 1 H, J = 2.2, 14.8 Hz, H-2 _trans ), 3.23 (dd, 1 H, J = 5.9, 14.8 Hz, H-2 _cis ), 4.66 (dd, 1 H, J = 2.2, 5.9 Hz, H-3), 6.72 (br d, 2 H, J = 8.6 Hz, H-3′,5′), 6.83 (d, 2 H, J = 8.7 Hz, H-3′′,5′′), 6.84 (dd, 1 H, J = 0.9, 8.3 Hz, H-7), 7.12 (br d, 2 H, J = 8.6 Hz, H-2′,6′), 7.29 (dd, 1 H, J = 0.9, 8.3 Hz, H-5), 7.37 (d, 2 H, J = 8.7 Hz, H-2′′,6′′), 7.72 (t, 1 H, J = 8.3 Hz, H-6), 8.18 (s, 1 H, H-7′′), 9.57 (s, 1 H, 4′-OH), 10.50 (s, 1 H, 4′′-OH), 12.71 (s, 1 H, 8-OH) ppm. ^¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 39.2 (C-3), 46.4 (C-2), 107.7 (C-5), 110.4 (C-8a), 111. 9 (C-7), 112.5 (C-9a), 116.0 (C-3′′,5′′), 115.9 (C-3′,5′), 125.2 (C-1′′), 125.7 (C-4), 128.1 (C-2′,6′), 130.8 (C-1′), 132.7 (C-2′′,6′′), 136.4 (C-6), 139.4 (C-7′′), 154.6 (C-4b), 156.5 (C-4′), 160.0 (C-4′′), 160.6 (C-8), 169.9 (C-4a), 179.8 (C-9), 191.8 (C-1) ppm. MS (ESI⁺): m/z (%) = 427 (15) [M + H]⁺, 449 (100) [M + Na]⁺, 465 (10) [M + K]⁺. HRMS (EI): m/z calcd for [C₂₆H₁₈O₆]⁺: 426.1103; found: 426.1116.

23

Physical Data of ( E )-4-(4-Chlorobenzylidene)-3-(4-chlorophenyl)-8-hydroxy-3,4-dihydro-1 H -xanthene-1,9 (2 H )-dione (9d)
Mp 110-113 ˚C. ^¹H NMR (300.13 MHz, CDCl₃): δ = 3.05 (dd, 1 H, J = 2.5, 15.5 Hz, H-2 _trans ), 3.15 (dd, 1 H, J = 5.6, 15.5 Hz, H-2 _cis ), 4.68 (dd, 1 H, J = 2.5, 5.6 Hz, H-3), 6.84 (dd, 1 H, J = 0.6, 8.4 Hz, H-7), 7.02 (dd, 1 H, J = 0.6, 8.4 Hz, H-5), 7.19 (br d, 2 H, J = 8.4 Hz, H-2′,6′), 7.26 (d, 2 H, J = 8.6 Hz, H-2′′,6′′), 7.30 (br d, 2 H, J = 8.4 Hz, H-3′,5′), 7.37 (d, 2 H, J = 8.6 Hz, H-3′′,5′′), 7.59 (t, 1 H, J = 8.4 Hz, H-6), 8.06 (s, 1 H, H-7′′), 12.54 (s, 1 H, 8-OH) ppm. ^¹³C NMR (75.47 MHz, CDCl₃): δ = 39.8 (C-3), 45.5 (C-2), 106.8 (C-5), 111.0 (C-8a), 112. 9 (C-7), 113.6 (C-9a), 128.3 (C-2′,6′), 129.3 (C-3′′,5′′), 129.6 (C-3′,5′), 129.7 (C-4), 130.7 (C-2′′,6′′), 132.4 (C-1′′), 133.7 (C-4′), 136.2 (C-6 and C-4′′), 137.9 (C-7′′), 138.3 (C-1′), 154.7 (C-4b), 161.7 (C-8), 168.7 (C-4a), 180.0 (C-9), 190.7 (C-1) ppm. MS (ESI⁺): m/z (%) = 463 (70) [(M + H)⁺, ^³5Cl], 465 (40) [(M + H)⁺, ^³5Cl^³7Cl], 467 (7) [(M + H)⁺, ^³7Cl], 485 (75) [(M + Na)⁺, ^³5Cl], 487 (45) [(M + Na)⁺, ^³5Cl^³7Cl], 489 (8) [(M + Na)⁺, ^³7Cl], 501 (15) [(M + K)⁺, ^³5Cl], 503 (10) [(M + K)⁺, ^³5Cl^³7Cl], 505 (2) [(M + K)⁺, ^³7Cl]. Anal. Calcd (%) for C₂₆H₁₆Cl₂O₄˙0.5H₂O (456.32): C, 66.12; H, 3.63. Found: C, 66.05; H, 3.58. HRMS (EI): m/z calcd for [C₂₆H₁₆ ^³5Cl₂O₄]⁺: 462.0426; found: 462.0406; m/z calcd for [C₂₆H₁₆ ^³5Cl^³7ClO₄]⁺: 464.0396; found: 464.0374; m/z calcd for [C₂₆H₁₆ ^³7Cl₂O₄]⁺: 466.0367; found: 466.0384.