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.

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

References and Notes

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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.

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