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.

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

References and Notes

1a Middleton E. Kandaswami C. Theoharides TC. Pharmacol. Rev.  2000,  52:  673 

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 

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%).

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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.

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 

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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%).

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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]⁺.

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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).