Download PDF
Synlett 2009(2): 306-309  
DOI: 10.1055/s-0028-1087523
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Facile Approach to 2-Substituted Isoflav-3-enes via Isoflavylium Salts

Jane Faragallaa, Andrew Heatonb, Renate Griffithc, John B. Bremner*a
a School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia
Fax: +61(2)42214287; e-Mail: john_bremner@uow.edu.au;
b Novogen Ltd., 140 Wicks Road, North Ryde, NSW 2113, Australia
c School of Medical Sciences/Pharmacology, University of NSW, Sydney, NSW 2052, Australia
Further Information

Publication History

Received 4 September 2008
Publication Date:
15 January 2009 (online)

    Permissions and Reprints All articles of this category

Abstract

A compact and regioselective approach to 2-substituted isoflav-3-enes based on a preformed 2-unsubstituted isoflavene is described. Isoflavene oxidation by hydride ion abstraction to the corresponding isoflavylium salt using trityl hexafluorophosphate followed by nucleophilic addition to the 2-position resulted in the introduction of a range of substituent groups in generally moderate to good yields.

Key words

nucleophilic additions - isoflavonoid - isoflavylium - isoflavene - trityl salts

    References and Notes

  • 1a Jain N. Kanojia RM. Xu J. Jian-Zhong G. Pacia E. Lai M.-T. Du F. Musto A. Allan G. Hahn D. Lundeen S. Sui Z. J. Med. Chem.  2006,  49:  3056 
    Search in Google Scholar
  • 1b Sarkar FH. Li Y. Cancer Metastasis Rev.  2002,  25:  265 
    Search in Google Scholar
  • 1c Fwu S.-Y. Chang C.-Y. Huang L.-J. Teng C.-M. Wang J.-P. Chen S.-C. Kuo S.-C. Chin. Pharm. J. (Taipei)  1999,  34:  255 
    Search in Google Scholar
  • 1d Emmanuel T. Dieudonne N. Tanyi MJ. Tanee FZ. Albert K. Jean-Claude M. Rosa GM. Carmen RM. Salvador M. Luis RJ. J. Nat. Prod.  2003,  66:  891 
    Search in Google Scholar
  • 1e Lozovaya VV. Lygin AV. Zernova OV. Li S. Hartman GL. Widholm JM. Plant Phys. Biochem.  2004,  42:  671 
    Search in Google Scholar
  • 1f Kuroda M. Mimaki Y. Sashida Y. Mae T. Kishida H. Nishiyama T. Tsukagawa M. Konishi E. Takahashi K. Kawada T. Nakagawa K. Kitahara M. Bioorg. Med. Chem. Lett.  2003,  13:  4267 
    Search in Google Scholar
  • 1g Martinez RM. Gimenez I. Lou JM. Mayoral JA. Alda JO. Am. J. Clin. Nutr.  1998,  68 (S1):  1354S 
    Search in Google Scholar
  • 2a Miyase T. Sano M. Nakai H. Muraoka M. Nakazawa M. Suzuki M. Yoshino K. Nishihara Y. Tanai J. Phytochemistry  1999,  52:  303 
    Search in Google Scholar
  • 2b Gamble JR. Xia P. Hahn CN. Drew JJ. Drogemuller CJ. Brown D. Vadas MA. Int. J. Cancer  2006,  118:  2412 
    Search in Google Scholar
  • 2c Alvero AB. O’Malley D. Brown D. Kelly G. Garg M. Chen W. Rutherford T. Mor G. Curr. Oncol. Rep.  2006,  8:  104 
    Search in Google Scholar
  • 3 Grese TA. Pennington LD. Tetrahedron Lett.  1995,  36:  8913 
    CrossrefSearch in Google Scholar
  • 4a Cook CE. Twine CE. J. Chem. Soc., Chem. Commun.  1968,  791 
  • 4b Cook CE. Wall ME. J. Org. Chem.  1968,  33:  2998 
    Search in Google Scholar
  • 4c Cook CE. Corley RC. Wall ME. J. Org. Chem.  1965,  30:  4114 
    Search in Google Scholar
  • 5 Alberola A. Andres C. Ortega AG. Pedrosa R. Vicente M. J. Heterocycl. Chem.  1986,  23:  1781 
    Search in Google Scholar
  • 6 Varma RS. Dahiya R. J. Org. Chem.  1998,  63:  8038 
    CrossrefSearch in Google Scholar
  • 7 Gauthier S. Caron B. Cloutier J. Dory YL. Favre A. Larouche D. Mailhot J. Ouellet C. Schwerdtfeger A. Leblanc G. Martel C. Simard J. Merand Y. Belanger A. Labrie C. Labrie F. J. Med. Chem.  1997,  40:  2117 
    CrossrefSearch in Google Scholar
  • 8a

    Trityl perchlorate has been used previously to access chromylium salts from the dihydro precursors8b but not, as far as we can ascertain, from 2-unsubstituted isoflav-3-enes. Isoflavylium salts can also be made, for example, by ring construction8c or by trityl salt mediated elimination of 2-substituted isoflav-3-enes8d

  • 8b Canalini G. Degani I. Fochi R. Spunta G. Ann. Chim. (Rome)  1967,  57:  1045 
    Search in Google Scholar
  • 8c Bouvier P. Andrieux J. Molho D. Tetrahedron Lett.  1974,  1033 
  • 8d Dean FM. Varma RS. J. Chem. Soc., Perkin Trans. 1  1982,  1193 
  • 9a

    Compound 1a is accessible from the commercially available precursors daidzein9c or daidzein diacetate9d,e

  • 9b Faragalla JE. PhD Thesis   University of Wollongong; Australia: 2005. 
  • 9c Heaton A, and Jeoffreys G. inventors; WO  2005103025.  ; Chem. Abstr. 2005, 143, 422198
  • 9d Heaton A, and Kumar N. inventors; WO  2000049009.  ; Chem. Abstr. 2000, 133, 177059
  • 9e Liepa AJ. Aust. J. Chem.  1981,  34:  2647 
    Search in Google Scholar
  • 11 Doodeman R. Rutjes FPJT. Hiemstra H. Tetrahedron Lett.  2000,  41:  5979 
    CrossrefSearch in Google Scholar
  • 12 Deprotection of TBS ethers by the related trityl tetrafluoroborate has been reported with the anion acting as a fluoride ion source. See: Metcalf BW. Burkhart JP. Jund K. Tetrahedron Lett.  1980,  21:  35 
    CrossrefSearch in Google Scholar
10

General Procedure (Table 1, Entry 3)
A mixture of powdered 3 Å MS, trityl hexafluorophosphate (2.2 mmol), and the isoflavene 1b (503 mg, 1.55 mmol) in freshly distilled, anhyd CH2Cl2 (50 mL, from CaH2) was stirred at r.t. under nitrogen for 30 min. Trimethylsilyl cyanide (0.480 g, 4.8 mmol) was then added, and the reaction mixture was stirred for a further hour at r.t. The reaction mixture was then filtered, washed with CH2Cl2, concentrated under vacuum filtration, and subjected to silica gel chromatography, using CH2Cl2 as the mobile phase to afford the product as a colorless crystalline solid (431 mg, 80%).

13

General Procedure (Table 2, Entry 1)
A mixture of powdered 3 Å MS, trityl hexafluorophosphate (2.2 mmol), and the isoflavene 1b (451 mg, 1.39 mmol) in freshly distilled, anhyd CH2Cl2 (50 mL, from CaH2) was stirred at r.t. under nitrogen for 30 min. The commercially available 2-trimethylsilylthiazole (0.403g, 2.564 mmol) was then added and the reaction mixture was stirred for a further hour at r.t. The reaction mixture was then filtered, washed with CH2Cl2, concentrated under vacuum filtration, and subjected to silica gel chromatography, using CH2Cl2 as the mobile phase to afford the product as a creamy white solid (430 mg, 76%).

14

Data for Selected Compounds7-Acetoxy-3- p -acetoxyphenyl-2-cyano-2 H -1-benzopyran (7b) White solid; mp 156-158 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 7.49 (d, J = 8.7 Hz, 2 H, H-2′/6′), 7.23 (d, J = 8.0 Hz,
1 H, H-5), 7.18 (d, J = 8.6 Hz, 2 H, H-3′/5′), 6.97 (s, 1 H, H4), 6.85 (dd, J = 2.5, 8.1 Hz, 1 H, H-6), 6.84 (s, 1 H, H-8), 6.01 (s, 1 H, H-2), 2.32 (s, 3 H, CH3), 2.30 (s, 3 H, CH3). ¹³C NMR (75 MHz, CDCl3): δ = 169.1 (C=O), 168.9 (C=O), 151.9 (C7), 151.1 (C8a), 150.3 (C4′), 131.9 (C3), 128.3 (C5), 126.2 (C2′), 125.9 (C1′), 122.4 (C3′), 122.3 (C4), 119.1 (C4a), 117.0 (C6), 110.5 (C8), 64.3 (C2), 21.1 (CH3). MS (CI+): m/z (%) = 323 (100) [MH+ - HCN]. Anal. Calcd (%) for C20H15NO5: C, 68.76; H, 4.33; N, 4.01. Found: C, 69.20; H, 4.34; N, 3.67.
7-Acetoxy-3- p -acetoxyphenyl-2-(2-thiazoyl)-2 H -1-benzopyran (8a)
Creamy white solid; mp 136-138 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 7.60 (br d, J = 2.7 Hz, 1 H, H-2′′), 7.37 (d, J = 8.7 Hz, 2 H, H-2′/6′), 7.23 (d, J = 6.3 Hz, 1 H, H-5), 7.08 (d, J = 2.7 Hz, 1 H, H-3′′), 6.93 (d, J = 8.4 Hz, 2 H, H-3′/5′), 6.89 (s, 1 H, H4), 6.57 (dd, J = 2.7, 8.4 Hz, 1 H, H-6), 6.53 (d, J = 2.4 Hz, 1 H,H-8), 6.44 (br s, 1 H, H-2), 2.13 (s, 3 H, CH3), 2.10 (s, 3 H, CH3). ¹³C NMR (75 MHz, CDCl3): δ = 169.5 (C=O), 169.3 (C=O), 169.3 (C1′′), 151.8 (C7), 151.7 (C8a), 150.8 (C4′), 143.3 (C4′′), 134.0 (C3), 131.5 (C1′), 127.9 (C5), 126.9 (C2′), 122.2 (C3′), 121.1 (C3′′), 120.9 (C4), 120.2 (C4a), 115.7 (C6), 110.6 (C8), 74.7 (C2), 21.3 (CH3). HRMS (CI+): m/z calcd for [M + H]+ C22H17NO5S + H: 408.0906; found: 408.0887.




7-Acetoxy-3- p -acetoxyphenyl-2-ethoxy-2 H -1-benzopyran (8f)
Creamy white solid; mp 134-136 ˚C. ¹H NMR (300 MHz, CDCl3): d = 7.53 (d, J = 9.0 Hz, 2 H, H-2′/6′), 7.23 (d, J = 8.4 Hz, 1 H, H-5), 7.12 (d, J = 8.4 Hz, 2 H, H-3′/5′), 6.98 (s, 1 H, H-4), 6.82 (d, J = 2.1 Hz, 1 H, H-8), 6.76 (dd, J = 8.4, 2.1 Hz, 1 H, H6), 5.95 (s, 1 H, H-2), 4.04-3.96 (m, 1 H, OCH 2CH3), 3.82-3.74 (m, 1 H, OCH 2CH3), 2.32 (s, 3 H, CH 3CO), 2.30 (s, 3 H, CH 3CO), 1.25 (t, J = 7.2 Hz, 3 H, CH2CH 3). ¹³C NMR (75 MHz, CDCl3): d = 169.5 (C=O), 169.3 (C=O), 151.4 (C7), 151.1 (C8a), 150.6 (C4′), 134.6 (C3), 129.7 (C1′), 128.0 (C5), 126.9 (C2), 122.1 (C3′), 121.5 (C4), 119.6 (C4a), 115.4 (C6), 110.4 (C8), 97.2 (C2), 64.1 (CH2CH3), 21.5 (CH3CO), 15.7 (CH2 CH3). MS (CI+): m/z (%) = 323 (100; 2-unsubstituted isoflavylium ion). Anal. Calcd (%) for C21H20O6: C, 68.40; H, 5.48. Found: C, 68.49; H, 5.53. 7-Acetoxy-3- p -acetoxyphenyl-2-[2-(7-acetoxy-3- p -acetoxyphenyl-2 H -1-benzopyranyl)ethynyl]-2 H -1-benzopyran (9) Solid; mp 237-238 ˚C (dec.). ¹H NMR (300 MHz, DMF-d 6; integrations and assignments for half dimer): d = 7.11 (d, J = 9.0 Hz, 2 H, H-2′/6′), 7.02 (d, J = 8.4 Hz, 1 H, H-5), 6.98 (s, 1 H, H4), 6.73 (dd, J = 2.4, 0.3 Hz, 1 H, H-8), 6.66 (d, J = 9.0 Hz, 1 H, H-3′), 6.53 (s, 1 H, H-2), 6.51 (dd, J = 8.4, 2.4 Hz, 1 H, H6), 1.94 (s, 3 H, CH3), 1.88 (s, 3 H, CH3). ¹³C NMR (75 MHz, DMSO-d 6): d = 169.2 (C=O), 169.1 (C=O), 151.8 (C7), 150.8 (C8a), 150.2 (C4′), 133.0 (C3), 128.4 (C1′), 128.2 (C5), 126.4 (C2′), 122.2 (C4), 121.5 (C3′), 119.4 (C6), 116.3 (C4a), 110.7 (C8), 92.5 (ethynyl C), 91.7 (C2), 20.4 (CH3), 20.3 (CH3). MS (ES+): m/z (%) = 323 (100; 2-unsubstituted isoflavylium ion). Anal. Calcd (%) for C41H34O10: C, 69.28; H, 4.60. Found: C, 69.27; H, 4.62.