Download PDF
Synlett 2007(12): 1897-1900  
DOI: 10.1055/s-2007-984525
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Diana C. G. A. Pinto, Artur M. S. Silva*, José A. S. Cavaleiro
Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
Fax: +351(234)370084; e-Mail: arturs@dq.ua.pt;
Further Information

Publication History

Received 9 May 2007
Publication Date:
25 June 2007 (online)

    Permissions and Reprints All articles of this category

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

  • 1a Middleton E. Kandaswami C. Theoharides TC. Pharmacol. Rev.  2000,  52:  673 
    CrossrefGoogle Scholar
  • 1b Vasselin DA. Westwell AD. Matthews CS. Bradshaw TD. Stevens MFG. J. Med. Chem.  2006,  49:  3973 
    CrossrefGoogle Scholar
  • 1c Comalada M. Ballester I. Bailón E. Sierra S. Xaus J. Gálvez J. Medina FS. Zarzuelo A. Biochem. Pharmacol.  2006,  72:  1010 
    CrossrefGoogle Scholar
  • 2 Bors W. Heller W. Michel C. Stettmaier K. In Handbook of Antioxidants   Cadenas E. Packer L. Marcel Dekker; New York: 1996.  p.409 
    Google Scholar
  • 3 Rice-Evans CA. Packer L. Flavonoids in Health and Disease   Marcel Dekker; New York: 1998.  p.447 
    Google Scholar
  • 4 Hogale MB. Pawar BN. Nikam BP. J. Indian Chem. Soc.  1987,  64:  486 
    Google Scholar
  • 5 Quintin J. Roullier C. Thoret S. Lewin G. Tetrahedron  2006,  62:  4038 
    CrossrefGoogle Scholar
  • 6a Fernandes E. Carvalho F. Silva AMS. Santos CMM. Pinto DCGA. Cavaleiro JAS. Bastos ML. J. Enzym. Inhib. Med. Chem.  2002,  17:  1756 
    CrossrefGoogle Scholar
  • 6b Fernandes E. Carvalho M. Carvalho F. Silva AMS. Santos CMM. Pinto DCGA. Cavaleiro JAS. Bastos ML. Arch. Toxicol.  2003,  77:  500 
    CrossrefGoogle Scholar
  • 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 
    CrossrefGoogle Scholar
  • 7 Pinto DCGA. Silva AMS. Almeida LMPM. Cavaleiro JAS. Elguero J. Eur. J. Org. Chem.  2002,  3807 ; and references cited therein
    CrossrefGoogle Scholar
  • 8 Pinto DCGA. Silva AMS. Cavaleiro JAS. New J. Chem.  2000,  24:  85 
    Google Scholar
  • 12a Gaydou EM. Bianchini J.-P. Bull. Soc. Chim. Fr.  1978,  2:  43 
    CrossrefGoogle Scholar
  • 12b Santos CMM. Silva AMS. Cavaleiro JAS. Eur. J. Org. Chem.  2003,  4575 
    CrossrefGoogle Scholar
  • 13 Looker JH. Edman JR. Dappen I. J. Heterocycl. Chem.  1964,  1:  141 
    Google Scholar
  • See, for example:
  • 14a Brito CM. Pinto DCGA. Silva AMS. Silva AMG. Tomé AC. Cavaleiro JAS. Eur. J. Org. Chem.  2006,  2558 
    Article in Thieme ConnectGoogle Scholar
  • 14b Silva VLM. Silva AMS. Pinto DCGA. Cavaleiro JAS. Synlett  2006,  1369 
    Article in Thieme ConnectGoogle Scholar
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]+.

11

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]+.

18

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