Baker-Venkataraman Rearrangement Under Microwave Irradiation: A New Strategy for the Synthesis of 3-Aroyl-5-hydroxyflavones

Abstract

Microwave irradiation selectively induces the Baker-Venkataraman rearrangement of 2′,6′-diaroyloxyacetophenones to give 3-aroyl-5-hydroxyflavones, in a very short reaction time. ­Under classical heating conditions these reactions afforded 5-hydroxyflavones as byproducts.

Key words

3-aroyl-5-hydroxyflavones - Baker-Venkataraman rearrangement - microwave irradiation - antioxidant activity

References and Notes

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• 1b Vasselin DA. Westwell AD. Matthews CS. Bradshaw TD. Stevens MFG. J. Med. Chem.  2006,  49:  3973 
• 1c Comalada M. Ballester I. Bailón E. Sierra S. Xaus J. Gálvez J. Medina FS. Zarzuelo A. Biochem. Pharmacol.  2006,  72:  1010 
• 2 Bors W. Heller W. Michel C. Stettmaier K. In Handbook of Antioxidants   Cadenas E. Packer L. Marcel Dekker; New York: 1996.  p.409 
• 3 Rice-Evans CA. Packer L. Flavonoids in Health and Disease   Marcel Dekker; New York: 1998.  p.447 
• 4 Hogale MB. Pawar BN. Nikam BP. J. Indian Chem. Soc.  1987,  64:  486 
• 5 Quintin J. Roullier C. Thoret S. Lewin G. Tetrahedron  2006,  62:  4038 
• 6a Fernandes E. Carvalho F. Silva AMS. Santos CMM. Pinto DCGA. Cavaleiro JAS. Bastos ML. J. Enzym. Inhib. Med. Chem.  2002,  17:  1756 
• 6b Fernandes E. Carvalho M. Carvalho F. Silva AMS. Santos CMM. Pinto DCGA. Cavaleiro JAS. Bastos ML. Arch. Toxicol.  2003,  77:  500 
• 6c Filipe P. Silva AMS. Morlière P. Brito CM. Patterson LK. Hug GL. Silva JN. Cavaleiro JAS. Mazière J.-C. Freitas JP. Santus R. Biochem. Pharmacol.  2004,  67:  2207 
• 7 Pinto DCGA. Silva AMS. Almeida LMPM. Cavaleiro JAS. Elguero J. Eur. J. Org. Chem.  2002,  3807 ; and references cited therein
• 8 Pinto DCGA. Silva AMS. Cavaleiro JAS. New J. Chem.  2000,  24:  85 
• 12a Gaydou EM. Bianchini J.-P. Bull. Soc. Chim. Fr.  1978,  2:  43 
• 12b Santos CMM. Silva AMS. Cavaleiro JAS. Eur. J. Org. Chem.  2003,  4575 
• 13 Looker JH. Edman JR. Dappen I. J. Heterocycl. Chem.  1964,  1:  141 
• See, for example:
• 14a Brito CM. Pinto DCGA. Silva AMS. Silva AMG. Tomé AC. Cavaleiro JAS. Eur. J. Org. Chem.  2006,  2558 
• 14b Silva VLM. Silva AMS. Pinto DCGA. Cavaleiro JAS. Synlett  2006,  1369 

9

Optimised Experimental Procedure A mixture of the 2′,6′-dihydroxyacetophenone (2a, 0.92 g, 6.05 mmol), the appropriate benzoic acid (13.31 mmol), 4-pyrrolidinopyridine (197 mg, 1.33 mmol), and N,N-dicyclohexylcarbodiimide (2.75 g, 13.33 mmol) in CH₂Cl₂ (50 mL) was stirred at r.t. for 12 h. The obtained dicyclohexylurea was filtered off and washed with CH₂Cl₂ (2 × 25 mL). The filtrate was evaporated to dryness and the residue recrystallised in from EtOH to provide the 2′,6′-diaroyloxyacetophenones 3a-c (3a, 83%; 3b, 78%; 3c, 80%).
A mixture of the 2′,4′,6′-trihydroxyacetophenone (2b, 0.86 g, 5.11 mmol), the appropriate benzoic acid (16.88 mmol), 4-pyrrolidinopyridine (250 mg, 1.69 mmol), and N,N-dicyclohexylcarbodiimide (3.48 g, 16.87 mmol) in CH₂Cl₂ (100 mL) was stirred at r.t. for 20 h. The obtained dicyclohexylurea was filtered off and washed with CH₂Cl₂ (2 × 30 mL). The filtrate was evaporated to dryness and the residue recrystallised in from EtOH to provide the 2′,4′,6′-triaroyloxyacetophenones 4a-c (4a, 80%; 4b, 85%; 4c, 79%).

10

Physical Data of 2′,4′,6′-Tribenzoyloxyacetophenone ( 4a) ¹H NMR (300.13 MHz, CDCl₃): δ = 2.51 (s, 3 H, 2-CH₃), 7.25 (s, 2 H, H-3′,5′), 7.52 (dd, 6 H, J = 7.6, 6.4 Hz, H-3,5 of 2′,4′,6′-OCOC₆H₅), 7.66 (t, 3 H, J = 7.6 Hz, H-4 of 2′,4′,6′-OCOC₆H₅), 8.15-8.20 (m, 6 H, H-2,6 of 2′,4′,6′-OCOC₆H₅) ppm. ¹³C NMR (75.47 MHz, CDCl₃): δ = 31.4 (2-CH₃), 114.6 (C-3′,5′), 125.8 (C-1′), 128.4 (C-1 of 2′,6′-OCOC ₆H₅), 128.6 (C-1 of 4′-OCOC ₆H₅), 128.7 (C-3,5 of 4′-OCOC ₆H₅), 128.8 (C-3,5 of 2′,6′-OCOC ₆H₅), 130.25 (C-2,6 of 4′-OCOC ₆H₅), 130.31 (C-2,6 of 2′,6′-OCOC ₆H₅), 134.0 (C-4 of 4′-OCOC ₆H₅), 134.2 (C-4 of 2′,6′-OCOC ₆H₅), 148.5 (C-2′,6′), 152.0 (C-4′), 164.1 (C=O of 4′-OCOC₆H₅), 164.2 (C=O of 2′,6′-OCOC₆H₅), 197.5 (C-1) ppm. MS (ES⁺): m/z (%) = 503 (100) [M + Na]⁺.

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Physical Data of 3′,4′-Dibenzyloxy-5-hydroxyflavone ( 5d)
¹H NMR (300.13 MHz, CDCl₃): δ = 5.25 and 5.26 (2 s, 2 × 2 H, 3′,4′-OCH ₂C₆H₅), 6.57 (s, 1 H, H-3), 6.80 (dd, 1 H, J = 8.3, 0.7 Hz, H-6), 6.94 (dd, 1 H, J = 8.3, 0.7 Hz, H-8), 7.02 (d, 1 H, J = 8.5 Hz, H-5′), 7.31-7.44 (m, 6 H, H-3,4,5 of 3′,4′-OCH₂C₆ H ₅), 7.45 (br s, 1 H, H-2′), 7.45-7.51 (m, 5 H, H-6′ and H-2,6 of 3′,4′-OCH₂C₆ H ₅), 7.52 (t, 1 H, J = 8.3 Hz, H-7), 12.64 (s, 1 H, 5-OH) ppm. ¹³C NMR (75.47 MHz, CDCl₃): δ = 70.9 (3′-OCH₂C₆H₅), 71.5 (4′-OCH₂C₆H₅), 104.8 (C-3), 106.9 (C-8), 110.7 (C-10), 111.3 (C-6), 112. 8 (C-2′), 114.0 (C-5′), 120.7 (C-6′), 123.9 (C-1′), 127.1 and 127.4 (C-2,6 of 3′,4′-OCH₂ C ₆H₅), 128.11 and 128.13 (C-4 of 3′,4′-OCH₂ C ₆H₅), 128.7 (C-3,5 of 3′,4′-OCH₂ C ₆H₅), 135.2 (C-7), 136.3 and 136.6 (C-1 of 3′,4′-OCH₂ C ₆H₅), 148.8 (C-3′), 152.3 (C-4′), 156.3 (C-9), 160.7 (C-5), 164.3 (C-2), 183.4 (C-4) ppm. MS (EI): m/z (%) = 450 (8) [M⁺]. HRMS (EI): m/z calcd for C₂₉H₂₂O₅: 450.1467; found: 450.1472.

15

Optimised Experimental Procedure A mixture of the appropriate 2′,6′-diaroyloxyacetophenone 3a-c and 4a-c (0.5 mmol) with anhyd K₂CO₃ (152 mg, 1.1 mmol) in anhyd pyridine (6 mL), was poured in a two-necked glassware apparatus equipped with a magnetic stirring bar, fibre-optic temperature control and reflux condenser, and was then irradiated in an Ethos SYNTH microwave (Milestone Inc.) at constant power of 400 W for 10 min. After that period the reaction mixture was poured into a mixture of ice and water and the pH was adjusted to 3-4 with diluted HCl. The obtained solid was filtered off and recrystallised from EtOH to provide the 3-aroyl-5-hydroxyflavones 5a-c and 6a-c; in several cases a purification by column chromatography was necessary, using CHCl₃ as eluent (5a, 70%; 5b, 69%; 5c, 72%; 6a, 72%; 6b, 68%; 6c, 73%).

16

Optimised Experimental Procedure BBr₃ (1.5 mol per benzyloxy group) was added to a solution of the appropriate 3-aroyl-5-hydroxyflavone 5c and 6c (0.3 mmol) in anhyd CH₂Cl₂ (25 mL) at low temperature (-70 °C). After the addition was complete, the cooling system was removed and the reaction mixture was stirred at r.t. for 24 h. Then, H₂O (50 mL) was added and the resulting reaction mixture was stirred at r.t. for 2-3 h. The obtained solid was filtered off and washed several times with H₂O and CH₂Cl₂; the expected 3-aroylflavones 7a,b were obtained in good yields (7a, 62%; 7b, 58%).
Physical Data of 3-(3,4-Dihydroxybenzoyl)-3′,4′,5,7-tetrahydroxyflavone ( 7b)
¹H NMR (300.13 MHz, DMSO-d ₆): δ = 6.25 (d, 1 H, J = 1.9 Hz, H-6), 6.48 (d, 1 H, J = 1.9 Hz, H-8), 6.73 (d, 1 H, J = 8.4 Hz, H-5′), 6.74 (d, 1 H, J = 8.2 Hz, H-5′′), 6.94 (dd, 1 H, J = 8.4, 2.2 Hz, H-6′), 7.06 (d, 1 H, J = 2.2 Hz, H-2′), 7.24 (dd, 1 H, J = 8.2, 2.0 Hz, H-6′′), 7.29 (d, 1 H, J = 2.0 Hz, H-2′′), 9.42, 9.86, and 10.06 (3 s, 4 H, 3′,4′,3′′,4′′-OH), 11.05 (s, 1 H, 7-OH), 12.48 (s, 1 H, 5-OH) ppm. ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 94.0 (C-8), 99.1 (C-6), 103.0 (C-10), 115.4 (C-2′,2′′), 115.7 (C-5′ and C-5′′), 118.7 (C-3), 120.7 (C-1′), 121.9 (C-6′), 123.2 (C-6′′), 128.8 (C-1′′), 145.4 (C-3′ and C-3′′), 149.2 (C-4′), 151.7 (C-4′′), 157.3 (C-9), 161.3 (C-2), 161.5 (C-5), 164.7 (C-7), 179.9 (C-4), 190.7 (C=O) ppm. MS (ES⁺): m/z (%) = 445 (63) [M + Na]⁺.

17

Physical Data of 3′,4′-Dibenzyloxy-3-(3,4-dibenzyloxybenzoyl)-5-hydroxyflavone ( 5c)
¹H NMR (300.13 MHz, CDCl₃): δ = 4.89 (s, 2 H, 3′-OCH ₂C₆H₅), 5.16 (s, 2 H, 4′-OCH ₂C₆H₅), 5.14 (s, 2 H, 3′′-OCH ₂C₆H₅), 5.21 (s, 2 H, 4′′-OCH ₂C₆H₅), 6.83 (dd, 1 H, J = 8.4, 0.7 Hz, H-6), 6.85 (d, 1 H, J = 8.6 Hz, H-5′), 6.88 (d, 1 H, J = 8.5 Hz, H-5′′), 6.96 (dd, 1 H, J = 8.4, 0.7 Hz, H-8), 7.16 (d, 1 H, J = 2.2 Hz, H-2′), 7.22 (dd, 1 H, J = 8.6, 2.2 Hz, H-6′), 7.23-7.43 (m, 20 H, H-2,3,4,5,6 of 3′,4′,3′′,4′′-OCH₂C₆ H ₅), 7.47 (dd, 1 H, J = 8.5, 2.0 Hz, H-6′′), 7.59 (t, 1 H, J = 8.4 Hz, H-7), 7.59 (d, 1 H, J = 2.0 Hz, H-2′′), 12.23 (s, 1 H, 5-OH) ppm. ¹³C NMR (75.47 MHz, CDCl₃): δ = 70.75 (4′-OCH₂C₆H₅), 70.78 (4′′-OCH₂C₆H₅), 71.0 (3′-OCH₂C₆H₅), 71.2 (3′′-OCH₂C₆H₅), 106.9 (C-8), 110.0 (C-10), 111.7 (C-6), 112.9 (C-5′′), 113.7 (C-5′), 114.1 (C-2′′), 114. 4 (C-2′), 120.0 (C-3), 122.7 (C-6′), 123.7 (C-1′), 125.0 (C-6′′), 127.0, 127.1, and 127.2 (C-2,6 of 3′,4′,3′′,4′′-OCH₂ C ₆H₅), 127.9, 128.0, and 128.1 (C-4 of 3′,4′,3′′,4′′-OCH₂ C ₆H₅), 128.49, 128.51, 128.60, and 128.64 (C-3,5 of 3′,4′,3′′,4′′-OCH₂ C ₆H₅), 130.3 (C1′′), 135.9 (C-7), 136.16, 136.24, 136.4, and 136.6 (C-1 of 3′,4′,3′′,4′′-OCH₂ C ₆H₅), 148.4 (C-3′), 148.8 (C-3′′), 151.8 (C-4′), 154.1 (C-4′′), 156.0 (C-9), 160.8 (C-5), 162.5 (C-2), 181.5 (C-4), 191.2 (C=O) ppm. MALDI-MS: m/z (%) = 789 (100) [M + Na]⁺.

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The structural characterisation of 3-aroyl-5-hydroxy-flavones 5a,b is according to the literature (ref. 7).